Journal articles: 'CLDN16'

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Hashimoto, Itaru, and Takashi Oshima. "Claudins and Gastric Cancer: An Overview." Cancers 14, no. 2 (January 7, 2022): 290. http://dx.doi.org/10.3390/cancers14020290.

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Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial–mesenchymal transition (EMT) and cell–cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell–cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and CLDN18–ARHGAP fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.

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Zheng, Aihua, Fei Yuan, Yanqin Li, Fangfang Zhu, Pingping Hou, Jianqing Li, Xijun Song, Mingxiao Ding, and Hongkui Deng. "Claudin-6 and Claudin-9 Function as Additional Coreceptors for Hepatitis C Virus." Journal of Virology 81, no. 22 (September 5, 2007): 12465–71. http://dx.doi.org/10.1128/jvi.01457-07.

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ABSTRACT Hepatitis C virus (HCV) is a global challenge to public health. Several factors have been proven to be critical for HCV entry, including the newly identified claudin-1 (CLDN1). However, the mechanism of HCV entry is still obscure. Presently, among the 20 members of the claudin family identified in humans so far, CLDN1 has been the only member shown to be necessary for HCV entry. Recently, we discovered that Bel7402, an HCV-permissive cell line, does not express CLDN1 but expresses other members of claudin family. Among these claudins, CLDN9 was able to mediate HCV entry just as efficiently as CLDN1. We then examined if other members of the claudin family could mediate entry. We show that CLDN6 and CLDN9, but not CLDN2, CLDN3, CLDN4, CLDN7, CLDN11, CLDN12, CLDN15, CLDN17, and CLDN23, were able to mediate the entry of HCV into target cells. We found that CLDN6 and CLDN9 are expressed in the liver, the primary site of HCV replication. We also showed that CLDN6 and CLDN9, but not CLDN1, are expressed in peripheral blood mononuclear cells, an additional site of HCV replication. Through sequence comparison and mutagenesis studies, we show that residues N38 and V45 in the first extracellular loop (EL1) of CLDN9 are necessary for HCV entry.

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Milatz, Susanne, Nina Himmerkus, Vera Christine Wulfmeyer, Hoora Drewell, Kerim Mutig, Jianghui Hou, Tilman Breiderhoff, et al. "Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na+ and Mg2+ transport." Proceedings of the National Academy of Sciences 114, no. 2 (December 27, 2016): E219—E227. http://dx.doi.org/10.1073/pnas.1611684114.

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The thick ascending limb (TAL) of Henle’s loop drives paracellular Na+, Ca2+, and Mg2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins that consist of four transmembrane segments, two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to a severe disturbance of renal ion homeostasis. We combined electrophysiological measurements on microperfused mouse TAL segments with subsequent analysis of claudin expression by immunostaining and confocal microscopy. Claudin interaction properties were examined using heterologous expression in the TJ-free cell line HEK 293, live-cell imaging, and Förster/FRET. To reveal determinants of interaction properties, a set of TAL claudin protein chimeras was created and analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na+ over Mg2+, whereas TJs dominated by cldn16 favor Mg2+ over Na+; (iii) cldn10b does not interact with other TAL claudins, whereas cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. We suggest the existence of at least two spatially distinct types of paracellular channels in TAL: a cldn10b-based channel for monovalent cations such as Na+ and a spatially distinct site for reabsorption of divalent cations such as Ca2+ and Mg2+.

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Madsen, Steffen S., Rebecca J. Bollinger, Melanie Brauckhoff, and Morten Buch Engelund. "Gene expression profiling of proximal and distal renal tubules in Atlantic salmon (Salmo salar) acclimated to fresh water and seawater." American Journal of Physiology-Renal Physiology 319, no. 3 (September 1, 2020): F380—F393. http://dx.doi.org/10.1152/ajprenal.00557.2019.

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Euryhaline teleost kidneys undergo a major functional switch from being filtratory in freshwater (FW) to being predominantly secretory in seawater (SW) conditions. The transition involves both vascular and tubular effects. There is consensus that the glomerular filtration rate is greatly reduced upon exposure to hyperosmotic conditions. Yet, regulation at the tubular level has only been examined sporadically in a few different species. This study aimed to obtain a broader understanding of transcriptional regulation in proximal versus distal tubular segments during osmotic transitions. Proximal and distal tubule cells were dissected separately by laser capture microdissection, RNA was extracted, and relative mRNA expression levels of >30 targets involved in solute and water transport were quantified by quantitative PCR in relation to segment type in fish acclimated to FW or SW. The gene categories were aquaporins, solute transporters, fxyd proteins, and tight junction proteins. aqp8bb1, aqp10b1, nhe3, sglt1, slc41a1, cnnm3, fxyd12a, cldn3b, cldn10b, cldn15a, and cldn12 were expressed at a higher level in proximal compared with distal tubules. aqp1aa, aqp1ab, nka-a1a, nka-a1b, nkcc1a, nkcc2, ncc, clc-k, slc26a6C, sglt2, fxyd2, cldn3a, and occln were expressed at a higher level in distal compared with proximal tubules. Expression of aqp1aa, aqp3a1, aqp10b1, ncc, nhe3, cftr, sglt1, slc41a1, fxyd12a, cldn3a, cldn3b, cldn3c, cldn10b, cldn10e, cldn28a, and cldn30c was higher in SW- than in FW-acclimated salmon, whereas the opposite was the case for aqp1ab, slc26a6C, and fxyd2. The data show distinct segmental distribution of transport genes and a significant regulation of tubular transcripts when kidney function is modulated during salinity transitions.

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Prot-Bertoye, Caroline, and Pascal Houillier. "Claudins in Renal Physiology and Pathology." Genes 11, no. 3 (March 10, 2020): 290. http://dx.doi.org/10.3390/genes11030290.

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Claudins are integral proteins expressed at the tight junctions of epithelial and endothelial cells. In the mammalian kidney, every tubular segment express a specific set of claudins that give to that segment unique properties regarding permeability and selectivity of the paracellular pathway. So far, 3 claudins (10b, 16 and 19) have been causally traced to rare human syndromes: variants of CLDN10b cause HELIX syndrome and variants of CLDN16 or CLDN19 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The review summarizes our current knowledge on the physiology of mammalian tight junctions and paracellular ion transport, as well as on the role of the 3 above-mentioned claudins in health and disease. Claudin 14, although not having been causally linked to any rare renal disease, is also considered, because available evidence suggests that it may interact with claudin 16. Some single-nucleotide polymorphisms of CLDN14 are associated with urinary calcium excretion and/or kidney stones. For each claudin considered, the pattern of expression, the function and the human syndrome caused by pathogenic variants are described.

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Rouka, Liakopoulos, Gourgoulianis, Hatzoglou, and Zarogiannis. "In-Depth Bioinformatic Study of the CLDN16 Gene and Protein: Prediction of Subcellular Localization to Mitochondria." Medicina 55, no. 8 (July 26, 2019): 409. http://dx.doi.org/10.3390/medicina55080409.

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Background and Objectives: The defects in the CLDN16 gene are a cause of primary hypomagnesemia (FHHNC), which is characterized by massive renal magnesium wasting, resulting in nephrocalcinosis and renal failure. The mutations occur throughout the gene’s coding region and can impact on intracellular trafficking of the protein or its paracellular pore forming function. To gain more understanding about the mechanisms by which CLDN16 mutations can induce FHHNC, we performed an in-depth computational analysis of the CLDN16 gene and protein, focusing specifically on the prediction of the latter’s subcellular localization. Materials and Methods: The complete nucleotide or amino acid sequence of CLDN16 in FASTA format was entered and processed in 14 databases. Results: One CpG island was identified. Twenty five promoters/enhancers were predicted. The CLDN16 interactome was found to consist of 20 genes, mainly involved in kidney diseases. No signal peptide cleavage site was identified. A probability of export to mitochondria equal to 0.9740 and a cleavable mitochondrial localization signal in the N terminal of the CLDN16 protein were predicted. The secondary structure prediction was visualized. Νo phosphorylation sites were identified within the CLDN16 protein region by applying DISPHOS to the functional class of transport. The KnotProt database did not predict any knot or slipknot in the protein structure of CLDN16. Seven putative miRNA binding sites within the 3’-UTR region of CLDN16 were identified. Conclusions: This is the first study to identify mitochondria as a probable cytoplasmic compartment for CLDN16 localization, thus providing new insights into the protein’s intracellular transport. The results relative to the CLDN16 interactome underline its role in renal pathophysiology and highlight the functional dependence of CLDNs-10, 14, 16, 19. The predictions pertaining to the miRNAs, promoters/enhancers and CpG islands of the CLDN16 gene indicate a strict regulation of its expression both transcriptionally and post-transcriptionally.

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Arabzadeh, Azadeh, Tammy-Claire Troy, and Kursad Turksen. "Role of the Cldn6 Cytoplasmic Tail Domain in Membrane Targeting and Epidermal Differentiation In Vivo." Molecular and Cellular Biology 26, no. 15 (August 1, 2006): 5876–87. http://dx.doi.org/10.1128/mcb.02342-05.

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ABSTRACT It is widely recognized that the claudin (Cldn) family of four tetraspan transmembrane proteins is crucial for tight junction assembly and permeability barrier function; however, the precise role of the tail and loop domains in Cldn function is not understood. We hypothesized that the cytoplasmic tail domain of Cldn6 is crucial for membrane targeting and hence epidermal permeability barrier (EPB) formation. To test this hypothesis via a structure-function approach, we generated a tail deletion of Cldn6 (CΔ187) and evaluated its role in epidermal differentiation and EPB formation through its forced expression via the involucrin (Inv) promoter in the suprabasal compartment of the transgenic mouse epidermis. Even though a functional barrier formed, Inv-CΔ187 mice displayed histological and biochemical abnormalities in the epidermal differentiation program and stimulation of epidermal cell proliferation in both the basal and suprabasal compartments of the interfolliclar epidermis, leading to a thickening of the epidermis after 1 week of age that persisted throughout life. Although some membrane localization was evident, our studies also revealed a significant amount of not only Cldn6 but also Cldn10, Cldn11, and Cldn18 in the cytoplasm of transgenic epidermal cells as well as the activation of a protein-unfolding pathway. These findings demonstrate that the overexpression of a tail truncation mutant of Cldn6 mislocalizes Cldn6 and other Cldn proteins to the cytoplasm and triggers a postnatal increase in proliferation and aberrant differentiation of the epidermis, emphasizing the importance of the Cldn tail domain in membrane targeting and function in vivo.

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Ko, Beom Seok, Hee Jeong Kim, Jong Han Yu, jong Won Lee, Byung Ho Sohn, Sung-Bae Kim, Gyungyub Gong, and Sei-Hyun Ahn. "Claudin 1, 3, 4, and 7 expression in triple-negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1070. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1070.

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1070 Background: Triple negative breast cancer (TNBC) often grows rapidly and has poor prognosis, with a high recurrence rate. Because conventional endocrine treatment and HER2 targeted therapy for TNBC is invalid, chemotherapy is the only systemic treatment for TNBC. It is known that several subtypes within the TNBC show different responses to chemotherapy, depending on the subtypes. Recently, a claudin (CLDN) low breast cancer has been identified, exhibiting low expressions of CLDNs 1, 3, 4 and 7. CLDNs are transmembrane proteins that seal tight junctions and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Methods: Surgically removed, formalin-fixed, paraffin-embedded breast cancers from 341 TNBC patients were analyzed to identify CLDN expression.They underwent wide local excision or mastectomy between March, 2004 and December, 2007 at the breast surgery unit of Asan Medical Central Hospital. Results: In our tumor series, we found 45.0% (153/339) of high expressing cases for CLDN1, 57.0% (192/337) for CLDN3, 57.6% (194/337) for CLDN4 and 44.0% (149/339) for CLDN7. Overall, we found 20.5% (70/341) of cases were within the low CLDN expression group and 79.5% (271/341) of tumors were within the high expression group of CLDN1, 3, 4 ,7. Although the high CLDN expression group was significantly associated with positive lymph node status and higher stage, there were no significant differences between CLDN low and high groups in disease free survival (p=0.477) or overall survival (p=0.253). Conclusions: CLDN high tumors are associated with poor prognosis features, but they are not an independent prognostic factor in TNBC patients. However, the mechanisms underlying the different roles of CLDNs in tumorigenesis are largely unclear. Studying the associations of these CLDNs with the TNBC subgroup of breast cancers might provide us with potential diagnostic biomarkers or therapeutic targets for cancer cells.

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Abu-Libdeh, Abdulsalam, Bassam Abu-Libdeh, and Ulla Abdulhag. "A Novel Mutation in the CLDN16 Gene in a Palestinian Family with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis." Journal of Child Science 07, no. 01 (January 2017): e32-e35. http://dx.doi.org/10.1055/s-0037-1604294.

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AbstractFamilial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal disorder characterized by excessive renal magnesium and calcium loss, bilateral nephrocalcinosis, and progressive renal failure, due to impaired tubular reabsorption in the thick ascending loop of Henle. FHHNC is caused by loss of function mutations in the claudin-16 gene (CLDN16) and claudin-19 gene (CLDN19). A 2-month-old male infant presented with convulsions during hypomagnesemia, hypocalcemia, and hypophosphatemia, biochemical findings were consistent with FHHNC. There is a positive family history of the death of a 12 years old sibling due to renal failure. Gene sequencing of the CLDN16 revealed a novel missense mutation with the replacement of T by C in codon 120 located in exon 2, predicting cysteine to arginine substitution p.Cys120Arg. This is the first description of this missense mutation and the first confirmation of FHHNC by molecular testing in a Palestinian family which enables genetic counseling and future prenatal diagnosis.

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Will, Constanze, Tilman Breiderhoff, Julia Thumfart, Marchel Stuiver, Kathrin Kopplin, Kerstin Sommer, Dorothee Günzel, et al. "Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting." American Journal of Physiology-Renal Physiology 298, no. 5 (May 2010): F1152—F1161. http://dx.doi.org/10.1152/ajprenal.00499.2009.

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Claudin-16 (CLDN16) is critical for renal paracellular epithelial transport of Ca2+ and Mg2+ in the thick ascending loop of Henle. To gain novel insights into the role of CLDN16 in renal Ca2+ and Mg2+ homeostasis and the pathological mechanisms underlying a human disease associated with CLDN16 dysfunction [familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), OMIM 248250], we generated a mouse model of CLDN16 deficiency. Similar to patients, CLDN16-deficient mice displayed hypercalciuria and hypomagnesemia. Contrary to FHHNC patients, nephrocalcinosis was absent in our model, indicating the existence of compensatory pathways in ion handling in this model. In line with the renal loss of Ca2+, compensatory mechanisms like parathyroid hormone and 1,25(OH)2D3 were significantly elevated. Also, gene expression profiling revealed transcriptional upregulation of several Ca2+ and Mg2+ transport systems including Trpv5, Trpm6, and calbindin-D9k. Induced gene expression was also seen for the transcripts of two putative Mg2+ transport proteins, Cnnm2 and Atp13a4. Moreover, urinary pH was significantly lower when compared with wild-type mice. Taken together, our findings demonstrate that loss of CLDN16 activity leads to specific alterations in Ca2+ and Mg2+ homeostasis and that CLDN16-deficient mice represent a useful model to further elucidate pathways involved in renal Ca2+ and Mg2+ handling.

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Müller, Dominik, P. Jaya Kausalya, Detlef Bockenhauer, Julia Thumfart, Iwan C. Meij, Michael J. Dillon, William van’t Hoff, and Walter Hunziker. "Unusual Clinical Presentation and Possible Rescue of a Novel Claudin-16 Mutation." Journal of Clinical Endocrinology & Metabolism 91, no. 8 (August 1, 2006): 3076–79. http://dx.doi.org/10.1210/jc.2006-0200.

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Abstract Context: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a dysfunction of Claudin-16 (CLDN16) and characterized by renal wasting of Mg2+ and Ca2+. Objective: The objectives of this study were to study the clinical parameters in suspected FHHNC patients, identify mutations in the CLDN16 gene, and analyze molecular defects associated with the mutant protein. Design, Setting, and Participants: CLDN16 genes from two siblings diagnosed with FHHNC were sequenced. Expression and characterization of the mutant protein in renal MDCK cells were studied. Outcome Measures: Standard urine and serum parameters to diagnose FHHNC were determined. Mutations in the CLDN16 gene were identified. The subcellular distribution of the mutant protein was analyzed by immunofluorescence microscopy. Results: Urine and blood analysis showed signs typical for FHHNC. One patient, in addition, presented with hypocalcemic tetany, a phenomenon so far not described for FHHNC. Both siblings carry a novel mutation in CLDN16, Y207X. The review of medical records showed that hypocalcemia is not uncommon in the early childhood of FHHNC patients. Expressed in MDCK cells, the Y207X mutant is not detected at tight junctions but instead is found in lysosomes and, to a lesser extent, the endoplasmic reticulum. Surface expression can be rescued by inhibiting clathrin-mediated internalization. Conclusions: We propose that mutations in CLDN16 are considered in childhood hypocalcemia. CLDN16 Y207X is transiently delivered to the plasma membrane but not retained and is rapidly retrieved by internalization. Inhibitors of endocytosis may provide novel therapeutic strategies.

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Zimmermann, Bettina, Christian Plank, Martin Konrad, Wolfgang Stöhr, Chara Gravou-Apostolatou, Wolfgang Rascher, and Jörg Dötsch. "Hydrochlorothiazide in CLDN16 mutation." Nephrology Dialysis Transplantation 21, no. 8 (April 4, 2006): 2127–32. http://dx.doi.org/10.1093/ndt/gfl144.

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Screnci, Brad, Lewis J. Stafford, Trevor Barnes, Kristen Shema, Samantha Gilman, Rebecca Rimkunas, Suzie Al Absi, et al. "Abstract 318: Atomic-level specificity of Claudin 6 monoclonal antibodies isolated for treating solid tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 318. http://dx.doi.org/10.1158/1538-7445.am2022-318.

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Abstract The tight junction protein Claudin 6 (CLDN6) is differentially expressed on cancer cells with almost no expression in healthy tissue, making it a valuable therapeutic target for many solid tumor cancers. Despite their potential as cancer therapeutics, very few CLDN6 monoclonal antibodies (MAbs) are in development, because MAbs with high affinity and specificity for CLDN6 are difficult to isolate. CLDN6 is structurally complex, with 4 transmembrane domains and 95% extracellular sequence conservation between human and mouse. Achieving MAb specificity for CLDN6 is especially challenging because its extracellular region strongly resembles those of 23 other human CLDN family members. In particular, the widely expressed CLDN9 differs from CLDN6 by only 3 extracellular residues. Using MAb discovery strategies specifically tailored to complex membrane proteins, including the use of virus-like particles (Lipoparticles), divergent species (chicken) immunization, and optimized phage display panning, we isolated 6 rare MAbs that recognize the native structure of CLDN6 with as low as picomolar affinity. The MAbs were screened against a Membrane Proteome Array containing ~6,000 membrane proteins and demonstrated specificity for CLDN6 with minimal cross-reactivity for CLDN9 or other CLDN family members. Epitope mapping using Shotgun Mutagenesis alanine scanning across the 220 residue CLDN6 sequence distinguished the binding sites of the MAbs from clinical-stage benchmarks. Atomic-level epitope mapping using comprehensive site-specific mutagenesis identified the γ carbon on CLDN6 residue Q156 as the critical structural mechanism enabling these MAbs to differentiate between CLDN6 and CLDN9 with high specificity. The CLDN6 MAbs identified here can be used to study CLDN6-positive cancers, including ovarian, endometrial, lung, and testicular cancer, and have the potential to be developed into highly selective therapeutics. Characterization of highly specific CLDN6 MAbs isolated for treatment of solid tumors MAb IM301 IM302 Benchmark (IMAB027, Astellas) VH CDR3 length (Kabat) 18 18 8 CLDN protein binding: Biosensor KD ± error, nM CLDN6 (target) 0.6 ± 0.03 < 0.001 0.5 ± 0.01 CLDN9 No binding No binding 3.6 ± .09 CLDN3 No binding No binding No binding CLDN4 No binding 146 ± 20 153 ± 6 Mouse CLDN6 binding Yes Yes Yes Cyno CLDN6 binding Yes Yes Yes Conformational epitope Yes Yes Yes Epitope topology Yes Yes Yes Critical CLDN6 epitope residues E48, E154, R158 E154, R158 F35, G37, S39 Citation Format: Brad Screnci, Lewis J. Stafford, Trevor Barnes, Kristen Shema, Samantha Gilman, Rebecca Rimkunas, Suzie Al Absi, Tim Phillips, Charles Azuelos, Katherine Slovik, Paige Muprhy, Daniel B. Harmon, Tom Charpentier, Benjamin J. Doranz, Joseph B. Rucker, Ross Chambers. Atomic-level specificity of Claudin 6 monoclonal antibodies isolated for treating solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 318.

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Himmerkus, Nina, Qixian Shan, Boeren Goerke, Jianghui Hou, Daniel A. Goodenough, and Markus Bleich. "Salt and acid-base metabolism in claudin-16 knockdown mice: impact for the pathophysiology of FHHNC patients." American Journal of Physiology-Renal Physiology 295, no. 6 (December 2008): F1641—F1647. http://dx.doi.org/10.1152/ajprenal.90388.2008.

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Claudin-16 is defective in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Claudin-16 knockdown (CLDN16 KD) mice show reduced cation selectivity in the thick ascending limb. The defect leads to a collapse of the lumen-positive diffusion voltage, which drives Ca2+ and Mg2+ absorption. Because of the reduced tight junction permeability ratio for Na+ over Cl−, we proposed a backleak of NaCl into the lumen. Systemic analysis had revealed lower blood pressure and a moderately increased plasma aldosterone concentration. In this study, we measured the amiloride-sensitive equivalent short-circuit current in isolated, perfused collecting ducts and found it increased by fivefold in CLDN16 KD mice compared with wild-type (WT) mice. Amiloride treatment unmasked renal Na+ loss in the thick ascending limb of the nephron. Under amiloride treatment, CLDN16 KD mice developed hyponatremia and the renal fractional excretion of Na+ was twofold higher in CLDN16 KD compared with WT mice. The loss of claudin-16 also resulted in increased urinary flow, reduced HCO3− excretion, and lower urine pH. We conclude that perturbation in salt and acid-base metabolism in CLDN16 KD mice has its origin in the defective cation permselectivity of the thick ascending limb of the nephron. This study has contributed to the still incomplete understanding of the symptoms of FHHNC patients.

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Chen, Lihe, Chun-Lin Chou, and Mark A. Knepper. "Targeted Single-Cell RNA-seq Identifies Minority Cell Types of Kidney Distal Nephron." Journal of the American Society of Nephrology 32, no. 4 (March 4, 2021): 886–96. http://dx.doi.org/10.1681/asn.2020101407.

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BackgroundProximal tubule cells dominate the kidney parenchyma numerically, although less abundant cell types of the distal nephron have disproportionate roles in water and electrolyte balance.MethodsCoupling of a FACS-based enrichment protocol with single-cell RNA-seq profiled the transcriptomes of 9099 cells from the thick ascending limb (CTAL)/distal convoluted tubule (DCT) region of the mouse nephron.ResultsUnsupervised clustering revealed Slc12a3+/Pvalb+ and Slc12a3+/Pvalb− cells, identified as DCT1 and DCT2 cells, respectively. DCT1 cells appear to be heterogeneous, with orthogonally variable expression of Slc8a1, Calb1, and Ckb. An additional DCT1 subcluster showed marked enrichment of cell cycle–/cell proliferation–associated mRNAs (e.g., Mki67, Stmn1, and Top2a), which fit with the known plasticity of DCT cells. No DCT2-specific transcripts were found. DCT2 cells contrast with DCT1 cells by expression of epithelial sodium channel β- and γ-subunits and much stronger expression of transcripts associated with calcium transport (Trpv5, Calb1, S100g, and Slc8a1). Additionally, scRNA-seq identified three distinct CTAL (Slc12a1+) cell subtypes. One of these expressed Nos1 and Avpr1a, consistent with macula densa cells. The other two CTAL clusters were distinguished by Cldn10 and Ptger3 in one and Cldn16 and Foxq1 in the other. These two CTAL cell types were also distinguished by expression of alternative Iroquois homeobox transcription factors, with Irx1 and Irx2 in the Cldn10+ CTAL cells and Irx3 in the Cldn16+ CTAL cells.ConclusionsSingle-cell transcriptomics revealed unexpected diversity among the cells of the distal nephron in mouse. Web-based data resources are provided for the single-cell data.

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Winkler, Lars, Rosel Blasig, Olga Breitkreuz-Korff, Philipp Berndt, Sophie Dithmer, Hans C. Helms, Dmytro Puchkov, et al. "Tight junctions in the blood–brain barrier promote edema formation and infarct size in stroke – Ambivalent effects of sealing proteins." Journal of Cerebral Blood Flow & Metabolism 41, no. 1 (February 13, 2020): 132–45. http://dx.doi.org/10.1177/0271678x20904687.

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The outcome of stroke is greatly influenced by the state of the blood–brain barrier (BBB). The BBB endothelium is sealed paracellularly by tight junction (TJ) proteins, i.e., claudins (Cldns) and the redox regulator occludin. Functions of Cldn3 and occludin at the BBB are largely unknown, particularly after stroke. We address the effects of Cldn3 deficiency and stress factors on the BBB and its TJs. Cldn3 tightened the BBB for small molecules and ions, limited endothelial endocytosis, strengthened the TJ structure and controlled Cldn1 expression. After middle cerebral artery occlusion (MCAO) and 3-h reperfusion or hypoxia of isolated brain capillaries, Cldn1, Cldn3 and occludin were downregulated. In Cldn3 knockout mice (C3KO), the reduction in Cldn1 was even greater and TJ ultrastructure was impaired; 48 h after MCAO of wt mice, infarct volumes were enlarged and edema developed, but endothelial TJs were preserved. In contrast, junctional localization of Cldn5 and occludin, TJ density, swelling and infarction size were reduced in affected brain areas of C3KO. Taken together, Cldn3 and occludin protect TJs in stroke, and this keeps the BBB intact. However, functional Cldn3, Cldn3-regulated TJ proteins and occludin promote edema and infarction, which suggests that TJ modulation could improve the outcome of stroke.

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Rahmani, Nasim, Saeed Talebi, Nakysa Hooman, and Arezou Karamzade. "Familial Hypomagnesemia with Hypercalciuria, Nephrocalcinosis, and Bilateral Chorioretinal Atrophy in a Patient with Homozygous p.G75S Variant in CLDN19." Journal of Pediatric Genetics 10, no. 03 (July 26, 2021): 230–35. http://dx.doi.org/10.1055/s-0041-1733852.

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Abstract Introduction Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare disorder caused by perturbation in renal reabsorption of magnesium and calcium. Biallelic pathogenic variants either in gene CLDN16 or CLDN19 are responsible for molecular defects. Most patients with CLDN19 variants have been associated with ocular involvements (FHHNCOI). Patient and Methods We had a pediatric patient with hypercalciuric hypomagnesemia and bilateral chorioretinal atrophy. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results Analysis of WES revealed a homozygous c.223G > A (p.G75S) variant in CLDN19. MutationTaster and Combined Annotation-Dependent Depletion support its deleterious effect and SHERLOC's criteria put it in pathogenic category. This variant is previously reported in compound heterozygous state with other known pathogenic variant. As far as we know, it is the first report of this variant in homozygous state. Conclusion The variant found in our patient is pathogenic and compatible with FHHNCOI characteristics. WES is an advantageous tool in molecular diagnosis and finding genetic pathology of this disease. In line with other reports, ocular abnormalities are variable in patients with CLDN19 mutations, and chronic kidney disease and retinal damages must be considered in this group.

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Tipsmark, Christian K., Andreas M. Nielsen, Maryline C. Bossus, Laura V. Ellis, Christina Baun, Thomas L. Andersen, Jes Dreier, Jonathan R. Brewer, and Steffen S. Madsen. "Drinking and Water Handling in the Medaka Intestine: A Possible Role of Claudin-15 in Paracellular Absorption?" International Journal of Molecular Sciences 21, no. 5 (March 8, 2020): 1853. http://dx.doi.org/10.3390/ijms21051853.

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When euryhaline fish move between fresh water (FW) and seawater (SW), the intestine undergoes functional changes to handle imbibed SW. In Japanese medaka, the potential transcellular aquaporin-mediated conduits for water are paradoxically downregulated during SW acclimation, suggesting paracellular transport to be of principal importance in hyperosmotic conditions. In mammals, intestinal claudin-15 (CLDN15) forms paracellular channels for small cations and water, which may participate in water transport. Since two cldn15 paralogs, cldn15a and cldn15b, have previously been identified in medaka, we examined the salinity effects on their mRNA expression and immunolocalization in the intestine. In addition, we analyzed the drinking rate and intestinal water handling by adding non-absorbable radiotracers, 51-Cr-EDTA or 99-Tc-DTPA, to the water. The drinking rate was >2-fold higher in SW than FW-acclimated fish, and radiotracer experiments showed anterior accumulation in FW and posterior buildup in SW intestines. Salinity had no effect on expression of cldn15a, while cldn15b was approximately 100-fold higher in FW than SW. Despite differences in transcript dynamics, Cldn15a and Cldn15b proteins were both similarly localized in the apical tight junctions of enterocytes, co-localizing with occludin and with no apparent difference in localization and abundance between FW and SW. The stability of the Cldn15 protein suggests a physiological role in water transport in the medaka intestine.

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McDermott, Martina S., Ke Wei Gong, Neil A. O'Brien, Dylan Conklin, Benjamin Hoffstrom, Ming Lu, Jun Zhang, et al. "Abstract 342: Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 342. http://dx.doi.org/10.1158/1538-7445.am2022-342.

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Abstract Background: Claudin 6 (CLDN6), a member of the claudin family of tight junction proteins, is expressed at high levels in multiple human malignancies including ovarian and endometrial cancers. Conversely it has little or no expression in normal tissues. This expression profile makes CLDN6 an ideal target for development of potential therapeutic antibody-drug conjugates (ADCs). This study describes the generation and preclinical characterization of an anti-CLDN6 ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to MMAE via a cleavable linker. Materials and Methods: A fully humanized anti-CLDN6 antibody was initially characterized for binding affinity, selectivity/specificity, internalization characteristics and in vivo efficacy. It was then conjugated to MMAE resulting in the potential therapeutic anti-CLDN6 ADC. The anti-tumor efficacy of the ADC was next assessed for anti-tumor efficacy in CLDN6 positive (CLDN6+) and negative (CLDN6-) xenografts and patient-derived xenograft (PDX) models of specific cancers including ovarian and endometrial cancer. Results: Selective binding of the ADC to CLDN6, without cross reactivity to other CLDN family members CLDN3, CLDN4 and CLDN9, was confirmed in human cancer cell lines and cells engineered to overexpress each protein. The ADC was also shown to rapidly internalize in CLDN6+ cells. Robust tumor regressions following treatment with the ADC were observed in CLDN6+ xenografts that were sustained beyond the treatment window. Conversely, there was limited to no activity of the ADC in CLDN6- xenografts models. In addition, the prevalence of CLDN6 expression in human ovarian and endometrial cancers was assessed by IHC in tissue microarrays and found to be 28% (ovarian epithelial carcinomas) and 11% (endometrial carcinomas), respectively. Discussion: Overall, these data suggest that our anti-CLDN6 ADC may be a promising treatment for patients with CLDN6+ tumors and it is currently in Phase I clinical testing. Citation Format: Martina S. McDermott, Ke Wei Gong, Neil A. O'Brien, Dylan Conklin, Benjamin Hoffstrom, Ming Lu, Jun Zhang, Tong Luo, Weiping Jia, Jenny J. Hong, Kevin Chau, Simon Davenport, Michael F. Press, Abram Handly-Santana, Joan S. Brugge, Ronny Drapkin, John A. Glaspy, Leonard Presta, Dennis J. Slamon. Development and characterization of a novel anti-CLDN6 antibody drug conjugate for the treatment of CLDN6 positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 342.

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Godron, Astrid, Jérôme Harambat, Valérie Boccio, Anne Mensire, Adrien May, Claire Rigothier, Lionel Couzi, et al. "Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis: Phenotype–Genotype Correlation and Outcome in 32 Patients with CLDN16 or CLDN19 Mutations." Clinical Journal of the American Society of Nephrology 7, no. 5 (March 15, 2012): 801–9. http://dx.doi.org/10.2215/cjn.12841211.

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Yang, Wancai, Yongchen Guo, Jim Lu, and Yonghua Bao. "Differential gene expression of tight-junction proteins and their correlation with PRSS8 and prognosis in colorectal cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15548-e15548. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15548.

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e15548 Background: Intestinal epithelia cells are made up of tight junctions, adheren junctions and desmosomes. As integral membrane proteins, the tight junction proteins (TJPs) claudins (CLDNs) and occludin (OCLN) are the most important TJPs that play a major role in maintaining the integrity of the intestinal epithelia and regulate several key signaling pathways in cancers. Dysregulation of tight junction and adheren junction has been shown to be associated with disruption of mucosa barriers, chronic colitis, early onset of colorectal carcinogenesis, epithelial mesenchymal transition and cancer metastasis. Our recent studies have shown that intestinal conditional knockout of the Press8 (protease serine 8) gene causes disruption of intestinal epithelial homeostasis, spontaneous inflammation and tumorigenesis in mouse intestine. Whether these pathogeneses are resulted from TJPs alterations and their correlation with PRSS8 are largely unknown. Methods: PRSS8 overexpression plasmid was transfected into colon cancer cell line HCT116 cells and proteomics was conducted. The Cancer Genome Atlas colorectal cancer (CRC) data set was deeply mined, and the correlation between TJPs’ alterations, PRSS8 and prognosis was analyzed. Results: In vitro proteomics assay showed that increasing expression of PRSS8 led to differential expression of cellular TJPs and adheren proteins, including upregulation of E-cadherin, TJP1 (ZO-1) and OCLN, and downregulation of RAC1, CDC42, RHOA, CLDND1, ARHGAP1, CTNNB1 and CTNNBL1. TCGA data mining showed differential gene expression of tight junction proteins. For instance, similar as PRSS8, most colonic mucosal TJPs, such as TJP1 (ZO-1), TJP3, OLCN, CLDN7, CLDN8 and PTPRJ, were significantly decreased in CRC tissues (n = 215), compared to normal mucosa (n = 22). Moreover, these reduced expression of TJPs were positively correlated with the reduction of PRSS8 and were inversely associated with prognosis. In contrast, another group of TJPs, such as TJP2, CLDN1, CLDN2 and CLDN12, was significantly increased in CRC tissues in comparison with the normal mucosa. These increases of expression were negatively correlated with PRSS8 expression and poor outcomes. More interestingly, the PTPRJ, a newly identified tumor suppressor, was dramatically reduced in metastatic CRC, compared to the primary CRC. Furthermore, the reduced expression of PTPRJ was linked to poor prognosis in the CRC patients. The underlying mechanisms of regulatory interaction between PRSS8 and TJPs are under investigation. Conclusions: TJPs are differentially expressed in CRC and the alterations were well correlated with PRSS8 and prognosis. Therefore, these two opposite groups of TJPs could be used as biomarkers for the monitoring of early onset colorectal carcinogenesis, progression and for the prediction of prognosis.

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Kang, Ju Hyung, Hyun Jin Choi, Hee Yeon Cho, Joo Hoon Lee, Il Soo Ha, Hae Il Cheong, and Yong Choi. "Familial hypomagnesemia with hypercalciuria and nephrocalcinosis associated with CLDN16 mutations." Pediatric Nephrology 20, no. 10 (July 27, 2005): 1490–93. http://dx.doi.org/10.1007/s00467-005-1969-7.

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Tajima, Toshihiro, Jun Nakae, and Kenji Fujieda. "Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC." Pediatric Nephrology 18, no. 12 (December 1, 2003): 1280–82. http://dx.doi.org/10.1007/s00467-003-1304-0.

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Zhang, Hejia, Chen Ling, and Xiaorong Liu. "A novel CLDN16 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis." Clinical Nephrology 92, no. 2 (August 1, 2019): 95–97. http://dx.doi.org/10.5414/cn109637.

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Godron, A., J. Harambat, A. Mensire, A. May, P. Merville, M. Godin, D. Chauveau, et al. "Syndrome d’hypomagnésémie, hypercalciurie, néphrocalcinose familiale (FHHNC) : histoire naturelle et corrélation phénotype génotype chez 29 patients porteurs de mutations des gènes CLDN16 ou CLDN19." Néphrologie & Thérapeutique 7, no. 5 (September 2011): 288–89. http://dx.doi.org/10.1016/j.nephro.2011.07.062.

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Kompatscher, Andreas, Jeroen H. F. de Baaij, Karam Aboudehen, Shayan Farahani, Lex H. J. van Son, Susanne Milatz, Nina Himmerkus, Gertjan C. Veenstra, René J. M. Bindels, and Joost G. J. Hoenderop. "Transcription factor HNF1β regulates expression of the calcium-sensing receptor in the thick ascending limb of the kidney." American Journal of Physiology-Renal Physiology 315, no. 1 (July 1, 2018): F27—F35. http://dx.doi.org/10.1152/ajprenal.00601.2017.

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Mutations in hepatocyte nuclear factor 1β (HNF1β) cause autosomal dominant tubulointerstitial kidney disease (ADTKD-HNF1β), and patients tend to develop renal cysts, maturity-onset diabetes of the young (MODY), and suffer from electrolyte disturbances, including hypomagnesemia, hypokalemia, and hypocalciuria. Previous HNF1β research focused on the renal distal convoluted tubule (DCT) to elucidate the ADTKD-HNF1β electrolyte phenotype, although 70% of Mg2+ is reabsorbed in the thick ascending limb of Henle’s loop (TAL). An important regulator of Mg2+ reabsorption in the TAL is the calcium-sensing receptor (CaSR). This study used several methods to elucidate the role of HNF1β in electrolyte reabsorption in the TAL. HNF1β ChIP-seq data revealed a conserved HNF1β binding site in the second intron of the CaSR gene. Luciferase-promoter assays displayed a 5.8-fold increase in CaSR expression when HNF1β was present. Expression of the HNF1β p.Lys156Glu mutant, which prevents DNA binding, abolished CaSR expression. Hnf1β knockdown in an immortalized mouse kidney TAL cell line (MKTAL) reduced expression of the CaSR and Cldn14 (claudin 14) by 56% and 48%, respectively, while Cldn10b expression was upregulated 5.0-fold. These results were confirmed in a kidney-specific HNF1β knockout mouse, which exhibited downregulation of the Casr by 81%. Cldn19 and Cldn10b expression levels were also decreased by 37% and 83%, respectively, whereas Cldn3 was upregulated by 4.6-fold. In conclusion, HNF1β is a transcriptional activator of the CaSR. Consequently, patients with HNF1β mutations may have reduced CaSR activity in the kidney, which could explain cyst progression and hyperabsorption of Ca2+ and Mg2+ in the TAL resulting in hypocalciuria.

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Narang, Gopal, Tim Shimon, Jonathan Moore, Megan Hager, Filippo Pinto e Vairo, Karen Stern, Mira Keddis, and Mitchell Humphreys. "Novel Variant in CLDN16: A Further Step in the Diagnosis of Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis—A Case Report." Uro 1, no. 3 (June 30, 2021): 76–81. http://dx.doi.org/10.3390/uro1030011.

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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy characterized by renal loss of calcium and magnesium leading to progressive renal failure. The disorder is caused by variants to the tight junction proteins claudin-16 and -19. While rare, this disorder causes a significant burden to patients based on its clinical manifestations of various electrolyte abnormalities, nephrocalcinosis, and early progression to renal failure. In this report we describe the diagnosis of a novel variant of CLDN16 which clinically presented with severe hypomagnesemia, hypocalcemia, nephrocalcinosis, and renal failure.

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Peco-Antic, Amira, Martin Konrad, Gordana Milosevski-Lomic, and Nikola Dimitrijevic. "Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: The first four patients in Serbia." Srpski arhiv za celokupno lekarstvo 138, no. 5-6 (2010): 351–55. http://dx.doi.org/10.2298/sarh1006351p.

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Introduction Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease characterized by excessive renal magnesium and calcium wasting, bilateral nehrocalcinosis and progressive renal failure. This is the first report of FHHNC of four patients in Serbia. Outline of Cases The first three patients were siblings from the same family. The index case, a 9-yearold girl, presented with severe growth retardation, polyuria and polydipsia, while her brothers, 11 and 7 years old, were disclosed during family member screening. The father had a urolithiasis when aged 18 years, while intermittent microhaematuria and bilateral microlithiasis persisted later on. The fourth patient, a 16-year-old boy with sporadic FHHNC was discovered to have increased proteinuria at routine examination of urine before registration for secondary school. He was well grown up, normotensive, but had moderate renal failure (CKD 3 stage), mild hypomagnesaemia and severe hypercalciuria and nephrocalcinosis. Beside typical clinical and biochemical data, the diagnosis of FHHNC was confirmed by mutation analysis of the CLDN16 gene; in all four affected individuals a homozygous CLDN16 mutation (Leu151Phe) was found. Treatment with magnesium supplementation resulted in the normalization of serum magnesium levels only in one patient (patient 4), but hypercalciuria persisted and renal failure progressed in all patients. Conclusion FHHNC is a rare cause of chronic renal failure. The first four patients with FHHNC in Serbia have been here described. The diagnosis of FHNNC based on the findings of nephrocalcinosis with hypomagnesiaemia and hypercalciuria, was confirmed by homozygous paracellin1-mutation exhibiting a Leu151Phe. .

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Yang, Hobin, Hayeon Park, Yong Jin Lee, Jun Young Choi, TaeEun Kim, Nirmal Rajasekaran, Saehyung Lee, et al. "Development of Human Monoclonal Antibody for Claudin-3 Overexpressing Carcinoma Targeting." Biomolecules 10, no. 1 (December 28, 2019): 51. http://dx.doi.org/10.3390/biom10010051.

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Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell–cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of antibodies against specific CLDN proteins is difficult, because CLDNs are four-transmembrane domain proteins with high homology among CLDN family members and species. Here, we developed a human IgG1 monoclonal antibody (h4G3) against CLDN3 through scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. The h4G3 recognized the native conformation of human and mouse CLDN3 without cross-reactivity to other CLDNs. The binding kinetics of h4G3 demonstrated a sub-nanomolar affinity for CLDN3 expressed on the cell surface. The h4G3 showed antibody-dependent cellular cytotoxicity (ADCC) according to CLDN3 expression levels in various cancer cells by the activation of FcγRIIIa (CD16a). The biodistribution of h4G3 was analyzed by intravenous injection of fluorescence-conjugated h4G3 which showed that it localized to the tumor site in xenograft mice bearing CLDN3-expressing tumors. These results indicate that h4G3 recognizes CLDN3 specifically, suggesting its value for cancer diagnosis, antibody-drug conjugates, and potentially as a chimeric antigen receptor (CAR) for CLDN3-expressing pan-carcinoma.

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Shapovalova, Alexandra I., Viktoria O. Polyakova, and Tatyana S. Kleimenova. "ВОЗРАСТНЫЕ ИЗМЕНЕНИЯ УРОВНЯ ЭКСПРЕССИИ МАРКЕРОВ ПЛОТНЫХ КОНТАКТОВ У ЖЕНЩИН ПОСЛЕ МИОМЭКТОМИИ." Siberian Journal of Life Sciences and Agriculture 13, no. 2 (April 29, 2021): 32–46. http://dx.doi.org/10.12731/2658-6649-2021-13-2-32-46.

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Обоснование. Миома матки представляет собой доброкачественные опухоли, образующиеся из гладкомышечных клеток. Клаудины (CLDN) являются основными белками плотных контактов, демонстрируя различную экспрессию в тканях, причем профиль экспрессии CLDN является репрезентативным. CLDN играют важнейшую роль в неопластических процессах, так как принимают участие в формировании единого сигнального пути между внеклеточным матриксом и внутриклеточным цитоскелетом. Цель. Изучить уровень экспрессии маркеров, отвечающих за функциональную активность плотных контактов клеток CLDN1, CLDN7 и CLDN10 в биоптатах интактного миометрия у женщин разных возрастных групп. Материалы и методы. Обследовано 90 пациенток в возрасте от 23 до 47 лет, которые были рандоминизированы на 6 групп. В первые три группы вошли 45 практически здоровых пациенток, в четвертую, пятую и шестую группы – женщины с миомой матки. И контрольные группы и пациентки с миомой матки были разделены на ранний, средний и поздний репродуктивный возраст. Исследование проводилось с разрешения этического комитета в отделении оперативной гинекологии с операционным блоком ФГБНУ «НИИ АГиР им. Д.О. Отта». (Директор – д.м.н., профессор Коган И.Ю.). Каждый участник подписывал форму информированного согласия на обследование. Проведён комплекс диагностических методик: анамнестические данные, клинико-гинекологическое обследование, эхография, эндоскопия, гистологическое исследование соскобов и макропрепаратов, удаленных во время операций. Далее материал исследовался при помощи иммунофлуоресцентного анализа. Статистическая обработка проводилась в программе «Excel 2010. Microsoft Office» и в аналитической программе «Statistica 10.0». Результаты. В результате иммунофлуоренсцентного анализа было выявлено, что уровень экспрессии маркеров плотных межклеточных контактов Claudin 1, Claudin 7 и Claudin 10 снижается в эпителии мембран клеток у женщин, страдающих миомой матки. Заключение. Таким образом, изменение функциональной активности плотных контактов приводит к нарушению связей между соседними клетками. Уровень экспрессии клаудинов может быть использован в качестве маркера и мишени для таргетной терапии.

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Sikora, P., M. Zaniew, L. Haisch, B. Pulcer, M. Szczepa ska, A. Moczulska, A. Rogowska-Kalisz, et al. "Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations." Nephrology Dialysis Transplantation 30, no. 4 (December 3, 2014): 636–44. http://dx.doi.org/10.1093/ndt/gfu374.

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Hanssen, O., E. Castermans, C. Bovy, L. Weekers, P. Erpicum, B. Dubois, V. Bours, J. M. Krzesinski, and F. Jouret. "Two novel mutations of the CLDN16 gene cause familial hypomagnesaemia with hypercalciuria and nephrocalcinosis." Clinical Kidney Journal 7, no. 3 (March 16, 2014): 282–85. http://dx.doi.org/10.1093/ckj/sfu019.

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Shinozaki, Aya, Tetsuo Ushiku, Teppei Morikawa, Rumi Hino, Takashi Sakatani, Hiroshi Uozaki, and Masashi Fukayama. "Epstein-Barr Virus-associated Gastric Carcinoma: A Distinct Carcinoma of Gastric Phenotype by Claudin Expression Profiling." Journal of Histochemistry & Cytochemistry 57, no. 8 (April 27, 2009): 775–85. http://dx.doi.org/10.1369/jhc.2009.953810.

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Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is a distinct subtype with characteristic clinicopathological features. To better characterize its cellular characteristics, 43 cases of EBV-associated GC, 68 cases of EBV-negative GC, and non-neoplastic gastric mucosa in adults and fetuses were examined immunohistochemically. We quantified the expression of the major tight-junction protein claudin (CLDN) -1, -3, -4, -7, and -18 together with gastric mucins (MUC5AC and MUC6), intestinal mucin (MUC2), and CD10. EBV-associated GC showed a high frequency of CLDN18 expression (84%) and a low frequency of CLDN3 expression (5%). This expression profile corresponded to that of normal gastric epithelium in adults and fetuses. Almost half of the EBV-associated GC cases demonstrated gastric mucin expression, whereas the other half lacked mucin or CD10 expression. In contrast, as demonstrated by the expression profiles of CLDN3 and CLDN18, EBV-negative GC comprised a heterogeneous group of four different CLDN phenotypes: gastric, intestinal, mixed, and an undifferentiated type with variable expression patterns of mucins. These results indicate that EBV-associated GC is considerably homogenous with regard to cellular differentiation and that it preserves well the nature of the cells of origin. EBV-associated GC may undergo distinct carcinogenic processes, which differ from those of EBV-negative GC.

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Deeb, Asma, Salima Abood, Job Simon, Hormazdiar Dastoor, Simon HS Pearce, and John A. Sayer. "A novel CLDN16 mutation in a large family with familial hypomagnesaemia with hypercalciuria and nephrocalcinosis." BMC Research Notes 6, no. 1 (2013): 527. http://dx.doi.org/10.1186/1756-0500-6-527.

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Stein, Laura, Nora Brunner, and Salah Amasheh. "Functional Analysis of Gastric Tight Junction Proteins in Xenopus laevis Oocytes." Membranes 12, no. 8 (July 23, 2022): 731. http://dx.doi.org/10.3390/membranes12080731.

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The epithelial barrier is crucial for proper gastrointestinal function, preventing the unwanted passage of solutes and therefore representing a prerequisite for vectorial transport. Claudin-4 and claudin-18.2, two critical tight junction proteins of the gastric epithelium, seal neighboring cells in a physically and mechanically challenging environment. As the Xenopus laevis oocyte allows the functional and molecular analyses of claudin interaction, we have addressed the hypothesis that this interaction is not only dependent on mechanical force but also on pH. We expressed human claudin-4 and claudin-18 in Xenopus oocytes, and analyzed them in a two-cell model approach. Cells were clustered in pairs to form contact areas expressing CLDN18 + CLDN18, CLDN4/18 + CLDN4/18, and compared to controls, respectively. Contact areas in cells incubated in medium at pH 5.5 and 7.4 were quantified by employing transmitted light microscopy. After 24 h at pH 5.5, clustering of CLDN18 + CLDN18 and CLDN4/18 + CLDN4/18-expressing oocytes revealed a contact area reduced by 45% and 32%, compared with controls, respectively. A further approach, high-pressure impulse assay, revealed a stronger tight junction interaction at pH 5.5 in oocyte pairs expressing CLDN18 + CLDN18 or CLDN4/18 + CLDN4/18 indicating a protective role of claudin-18 for tight junction integrity during pH challenge. Thus, our current analysis of gastric tight junction proteins further establishes oocytes as an expression and two-cell screening model for tight junction integrity analysis of organ- and tissue-specific claudins by the characterization of homo- and heterophilic trans-interaction dependent on barrier effectors.

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Prikhodina, Larisa, Marina Lebedenkova, Olga Katysheva, and Mato Nagel. "SP913HEPATOBLASTOMA IN A CHILD WITH FAMILIAL HYPOMAGNESAEMIA, HYPERCALCIURIA AND NEPHROCALCINOSIS CAUSED BY MUTATION IN CLDN16 GENE." Nephrology Dialysis Transplantation 30, suppl_3 (May 2015): iii677. http://dx.doi.org/10.1093/ndt/gfv203.51.

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Meij, I. C. "Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss." Nephrology Dialysis Transplantation 18, no. 3 (March 1, 2003): 512–16. http://dx.doi.org/10.1093/ndt/18.3.512.

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Chakraborty, Papia, F. William Buaas, Manju Sharma, Benjamin E. Smith, Anne R. Greenlee, Stephen M. Eacker, and Robert E. Braun. "Androgen-Dependent Sertoli Cell Tight Junction Remodeling Is Mediated by Multiple Tight Junction Components." Molecular Endocrinology 28, no. 7 (July 1, 2014): 1055–72. http://dx.doi.org/10.1210/me.2013-1134.

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Sertoli cell tight junctions (SCTJs) of the seminiferous epithelium create a specialized microenvironment in the testis to aid differentiation of spermatocytes and spermatids from spermatogonial stem cells. SCTJs must be chronically broken and rebuilt with high fidelity to allow the transmigration of preleptotene spermatocytes from the basal to adluminal epithelial compartment. Impairment of androgen signaling in Sertoli cells perturbs SCTJ remodeling. Claudin (CLDN) 3, a tight junction component under androgen regulation, localizes to newly forming SCTJs and is absent in Sertoli cell androgen receptor knockout (SCARKO) mice. We show here that Cldn3-null mice do not phenocopy SCARKO mice: Cldn3−/− mice are fertile, show uninterrupted spermatogenesis, and exhibit fully functional SCTJs based on imaging and small molecule tracer analyses, suggesting that other androgen-regulated genes must contribute to the SCARKO phenotype. To further investigate the SCTJ phenotype observed in SCARKO mutants, we generated a new SCARKO model and extensively analyzed the expression of other tight junction components. In addition to Cldn3, we identified altered expression of several other SCTJ molecules, including down-regulation of Cldn13 and a noncanonical tight junction protein 2 isoform (Tjp2iso3). Chromatin immunoprecipitation was used to demonstrate direct androgen receptor binding to regions of these target genes. Furthermore, we demonstrated that CLDN13 is a constituent of SCTJs and that TJP2iso3 colocalizes with tricellulin, a constituent of tricellular junctions, underscoring the importance of androgen signaling in the regulation of both bicellular and tricellular Sertoli cell tight junctions.

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Senga, Kazunori, Keith E. Mostov, Toshihiro Mitaka, Atsushi Miyajima, and Naoki Tanimizu. "Grainyhead-like 2 regulates epithelial morphogenesis by establishing functional tight junctions through the organization of a molecular network among claudin3, claudin4, and Rab25." Molecular Biology of the Cell 23, no. 15 (August 2012): 2845–55. http://dx.doi.org/10.1091/mbc.e12-02-0097.

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During development, epithelial progenitors establish intercellular junctions, including tight junctions (TJs), and form three-dimensional (3D) tissue structures, which are often associated with luminal structures. Here we identify grainyhead-like 2 (Grhl2) as a transcription factor that regulates the size of luminal space surrounded by polarized epithelial cells. We show that HPPL, a liver progenitor cell line, transfected with Grhl2 cDNA forms remarkably larger cysts than the control cells in 3D cultures. We find that Grhl2 up-regulates claudin (Cldn) 3 and Cldn4, and their functions are necessary for the formation of large cysts. Overexpression of Cldn3 alone induces the cyst expansion. In contrast, expression of Cldn4 alone does not induce expansion, as it is not localized at TJs. Of interest, Rab25, another Grhl2 target, not only increases the Cldn4 protein, but also enhances its localization at TJs. Taken together, the results indicate that Grhl2 regulates epithelial morphogenesis through transcriptional up-regulation of Cldn3 and Cldn4, as well as of Rab25, which increases the Cldn4 protein and its localization at TJs. The results reveal a molecular network regulating epithelial lumen formation organized by Grhl2.

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Guran, T., T. Akcay, A. Bereket, Z. Atay, S. Turan, L. Haisch, M. Konrad, and K. P. Schlingmann. "Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes." Nephrology Dialysis Transplantation 27, no. 2 (June 9, 2011): 667–73. http://dx.doi.org/10.1093/ndt/gfr300.

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Rucker, Joseph, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nick Molino, Kristen Shema, Kyle Guldner, Alyssa Cunningham, Ross Chambers, and Riley Payne. "Abstract 2892: Development of claudin 6 bispecific antibodies for treatment of ovarian cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2892. http://dx.doi.org/10.1158/1538-7445.am2022-2892.

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Abstract There is growing interest in applying antibody modalities including bispecifics, antibody-drug conjugates, and CART to solid tumors. However, identifying appropriate tumor-specific targets that avoid adverse effects in healthy tissue has been challenging. The tight junction protein Claudin 6 (CLDN6) is a validated therapeutic target for many solid tumor types, including ovarian, endometrial, testicular, and gastric. It is differentially expressed on cancer cells with no reported expression in normal, healthy tissue. Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. There are 26 human CLDN family members, and most are broadly expressed and highly conserved. The extracellular region of CLDN6 closely resembles the widely expressed CLDN9 (3 amino acids different). The few CLDN6 MAbs in clinical development have demonstrated significant binding to other CLDN family members and most have now been halted from development. Using Integral Molecular’s MPS antibody discovery platform, we have been able to isolate, and optimize rare antibodies against CLDN6 that do not cross-react with other CLDN family members. The exquisite specificity of our CLDN6 antibodies makes them amenable to use as the tumor-targeting arm of bispecific T-Cell Engagers. Starting with highly specific CLDN6 antibodies with a range of affinities, we engineered a large set (> 50) of CLDN6xCD3 bispecific antibodies (CLDN6 bispecifics) using multiple formats and CD3 arms that encompass different valencies and geometries. We designed the CLND6 arms to include antibody moieties with different affinities, epitopes, and stoichiometries, as these factors are expected to play a critical role in the potency of these molecules both in in vitro and in vivo. The full panel of bispecifics has been functionally tested in in vitro T cell cytotoxicity assays cells and has demonstrated potent killing of CLDN6-expressing cells with minimal killing of cells expressing other closely related claudin family members. We have also extensively characterized this panel of bispecific antibodies for detailed binding to both CD3 and CLDN6, selectivity against closely related claudin family members, and developability. The bispecifics were also screened for specificity against ~6,000 membrane proteins, representing > 95% of the entire human membrane proteome. Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tumors are lacking. Ovarian cancer alone kills 14,000 people each year, and many patients do not respond to currently available treatments. The exquisite specificity of our CLDN6xCD3 bispecifics suggests their potential to address the need for potent therapeutic modalities for ovarian and other cancers without compromising patient safety. Citation Format: Joseph Rucker, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nick Molino, Kristen Shema, Kyle Guldner, Alyssa Cunningham, Ross Chambers, Riley Payne. Development of claudin 6 bispecific antibodies for treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2892.

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Adil, Mir S., Varun Parvathagiri, Arti Verma, Fang Liu, Madhuri Rudraraju, S. Priya Narayanan, and Payaningal R. Somanath. "Claudin-17 Deficiency in Mice Results in Kidney Injury Due to Electrolyte Imbalance and Oxidative Stress." Cells 11, no. 11 (May 29, 2022): 1782. http://dx.doi.org/10.3390/cells11111782.

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The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood–tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge about CLDN17 in physiology and pathology is limited. The current study investigated how Cldn17 deficiency in mice affects blood electrolytes and kidney structure. Cldn17−/− mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth. Adult Cldn17−/− mice displayed electrolyte imbalance, oxidative stress, and injury to the kidneys. Ingenuity pathway analysis followed by RNA-sequencing revealed hyperactivation of signaling pathways and downregulation of SOD1 expression in kidneys associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in the maintenance of electrolytes and reactive oxygen species across the blood-tissue barrier.

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Lv, Fang, Xiao-jie Xu, Jian-yi Wang, Yi Liu, Yan Jiang, Ou Wang, Wei-bo Xia, Xiao-ping Xing, and Mei Li. "A novel mutation in CLDN16 results in rare familial hypomagnesaemia with hypercalciuria and nephrocalcinosis in a Chinese family." Clinica Chimica Acta 457 (June 2016): 69–74. http://dx.doi.org/10.1016/j.cca.2016.04.004.

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Li, Zhan Dong, Xiangtian Yu, Zi Mei, Tao Zeng, Lei Chen, Xian Ling Xu, Hao Li, Tao Huang, and Yu-Dong Cai. "Identifying luminal and basal mammary cell specific genes and their expression patterns during pregnancy." PLOS ONE 17, no. 4 (April 29, 2022): e0267211. http://dx.doi.org/10.1371/journal.pone.0267211.

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Mammary gland is present in all mammals and usually functions in producing milk to feed the young offspring. Mammogenesis refers to the growth and development of mammary gland, which begins at puberty and ends after lactation. Pregnancy is regulated by various cytokines, which further contributes to mammary gland development. Epithelial cells, including basal and luminal cells, are one of the major components of mammary gland cells. The development of basal and luminal cells has been observed to significantly differ at different stages. However, the underlying mechanisms for differences between basal and luminal cells have not been fully studied. To explore the mechanisms underlying the differentiation of mammary progenitors or their offspring into luminal and myoepithelial cells, the single-cell sequencing data on mammary epithelia cells of virgin and pregnant mouse was deeply investigated in this work. We evaluated features by using Monte Carlo feature selection and plotted the incremental feature selection curve with support vector machine or RIPPER to find the optimal gene features and rules that can divide epithelial cells into four clusters with different cell subtypes like basal and luminal cells and different phases like pregnancy and virginity. As representations, the feature genes Cldn7, Gjb6, Sparc, Cldn3, Cited1, Krt17, Spp1, Cldn4, Gjb2 and Cldn19 might play an important role in classifying the epithelial mammary cells. Notably, seven most important rules based on the combination of cell-specific and tissue-specific expressions of feature genes effectively classify the epithelial mammary cells in a quantitative and interpretable manner.

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Zhuang, Xinguo, Wen G. Jiang, Fiona Ruge, Eleri Davies, Bing Xu, and Tracey A. Martin. "Abstract P2-11-29: The Expression of Claudin-10 in relationship with Her family members in patients with breast cancer." Cancer Research 83, no. 5_Supplement (March 1, 2023): P2–11–29—P2–11–29. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-11-29.

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Abstract Introduction. Claudin-10 (CLDN10), a member of the Claudin tight junction (TJ) protein family, was initially known as Oligodendrocyte-Specific Protein-Like (OSP-L). The distribution of CLDN10 in the body is not ubiquitous and is seen more abundantly in kidney and brain and at modest levels in mammary tissues. Limited information suggests that in cells where CLDN10 is expressed, it interacts with other family members including CLDN-11, 12, 16, 17 and the subcoat zonula occludens (ZO-1 and ZO-3) to regulate TJ functions. The role played by CLDN10 in cancer is not clear but there are suggestions that it is a favourable indicator for disease progression in kidney and gastric cancers but an adverse indictor in hormone related cancers such as thyroid cancer. The role of CLDN10 in breast cancer is otherwise not known. We have investigated the expression profile and in particular in its relationship with hormone receptor status. Methods. We carried out CLDN10 transcript and protein analyses by way of quantitative PCR and immunohistochemistry on an established cohort of fresh frozen mammary tissues and breast cancer tissues. Expression was analysed via QPCR against the staging, histology, clinical outcome, hormone status including ER and Her family members, and also its known interactive TJ molecules available to our database. Results. Compared with its interactive TL partner molecules, CLDN10 was expressed at relatively low levels in mammary tissues. There was no significant difference in CLDN10 transcript levels between normal tissues and tumour tissues. Patients with high levels of CLDN10 in breast tumours had significantly shorter overall survival (OS) (p=0.041) and disease free survival (DFS) (p=0.026). In our cohort, we found a significant correlation between levels of CLDN10 and Her-1/EGFR (r=0.201, p=0.026) and Her3 (r=0.935, p< 0.0001), but not with Her-2 nor with Her-4. It was also surprised to find that CLDN10 did not correlated with the ZO-1, ZO-3, CLDN11, 12, 14, and 17. We then identified a subgroup of patients with low levels of CLDN10 and their overall survival (OS) and disease free survival (DFS) which were significantly correlated with Her-1/Her-3 expression status (p< 0.0001 for both OS and DFS). CLDN10, amongst the clinical, pathological and hormone receptor status, is an independent prognostic factor for DFS (p=0.008, Hazard Ratio (HR) =4.228 (95% CI 1.449-12.342)) and for OS (p=0.025, HR=3.917 (95% CI 1.187-12.924)). The predictive power for triple negative breast cancer (TNBC) and non-TNBC by CLDN10 otherwise remained similar and not statistically significant. It was noted that stratification by ER and Her-2 did not contribute to the value of independency. Conclusion. CLDN10, although expressed at relative lower levels in breast cancer, is a contributing factor to the survival of the patients. Together with the status of EGFR and Her-3, it makes an independent prognostic factor for both the overall survival and disease free survival of the patients. Citation Format: Xinguo Zhuang, Wen G. Jiang, Fiona Ruge, Eleri Davies, Bing Xu, Tracey A. Martin. The Expression of Claudin-10 in relationship with Her family members in patients with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-29.

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Qu, Huinan, Qiu Jin, and Chengshi Quan. "CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers." International Journal of Molecular Sciences 22, no. 24 (December 14, 2021): 13416. http://dx.doi.org/10.3390/ijms222413416.

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Claudins (CLDNs) are the most important tight junction proteins, which are mainly expressed in endothelial cells or epithelial cells in a tissue-specific manner. As a member of the CLDNs family, CLDN6 is highly expressed in fetal tissues such as the stomach, pancreas, lung, and kidney, but is not expressed in corresponding adult tissues. The expression of CLDN6 is regulated by a variety of factors, including but not limited to stimuli and transcription factors, DNA methylation, and post-translational modifications. CLDN6 has been found to have a key role in the formation of barriers, especially the lung epithelial barrier and the epidermal permeability barrier (EPB). Importantly, the roles of CLDN6 in cancers have gained focus and are being investigated in recent years. Strong evidence indicates that the altered expression of CLDN6 is linked to the development of various cancers. Malignant phenotypes of tumors affected by CLDN6 include proliferation and apoptosis, migration and invasion, and drug resistance, which are regulated by CLDN6-mediated key signaling pathways. Given the important role in tumors and its low or no expression in normal tissues, CLDN6 is an ideal target for tumor therapy. This review aims to provide an overview of the structure and regulation of CLDN6, and its traditional barrier function, with a special emphasis on its emerging roles in cancers, including its impact on the malignant phenotypes, signal-modulating effects, the prognosis of tumor patients, and clinical applications in cancers.

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Eltan, Mehmet, Zehra Yavas Abali, Ayberk Turkyilmaz, Ibrahim Gokce, Saygın Abali, Ceren Alavanda, Ahmet Arman, et al. "Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features." Calcified Tissue International 110, no. 4 (November 11, 2021): 441–50. http://dx.doi.org/10.1007/s00223-021-00928-y.

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Hwang, I., and E. B. Jeung. "98 THE EXPRESSION OF TIGHT JUNCTION GENES IN THE PLACENTA BY CALCIUM OR VITAMIN D DEFICIENCY IN WILD TYPE AND CaBP-9k OR CaBP-28k KNOCKOUT MICE." Reproduction, Fertility and Development 25, no. 1 (2013): 197. http://dx.doi.org/10.1071/rdv25n1ab98.

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The placenta is responsible for calcium transport from mother to fetus. Tight junction genes are responsible for the passive paracellular pathway, which is one of the major calcium transport pathways. Therefore, we examined whether the tight junction genes are differently expressed in the placenta by calcium, vitamin D, or both deficiency. We also investigated the correlation between transcellular transport and paracellular transport by using calbindin-D9k (CaBP-9k), calbindin-D28K (CaBP-28k), or both knockout (KO) mice. We administrated C57BL/6 wild type and CaBP-D9K, CaBP-D28K KO, or both mice with calcium, vitamin D, or both deficiency diets for 19 days (during pregnant Day 0 to 18). The expression levels and localization of tight junction genes including zona occludens 1 (Zo-1), junction adhesion molecules A (Jam-A), and claudins (Cldn) were tested. The mRNA and protein expression of these genes were investigated by real-time PCR and Western blotting assay. Five samples from 3 animals for each treated group were used and the data analyzed using a one-way ANOVA. P-values <0.05 were considered statistically significant. The localization of the genes was also examined by immunohistochemistry. The mRNA and protein expressions of Cldn1 were increased in calcium and calcium/vitamin D deficient CaBP-D9K KO mice and in calcium/vitamin D deficient CaBP-D9/28K mice, whereas those of Zo-1 and Jam-A were not affected. Gene Cldn5 mRNA expression showed a decrease in CaBP-9k, CaBP-28k, or both KO mice compared with wild type mice. Interestingly, Cldn5 mRNA expression was augmented in vitamin D or calcium deficient CaBP-D9K KO mice. Other tested Cldns did not show significant changes in any dietary or CaBP KO conditions. All the tight junction genes were localized in the trophoblast layer of the placenta. Taken together, the expression of tight junction genes was dynamically regulated by different dietary conditions and in the condition that transcellular calcium transport was altered by ablation of CaBPs, suggesting that these genes were involved in the placental calcium homeostasis.

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van Megen, Wouter H., Megan R. Beggs, Sung-Wan An, Patrícia G. Ferreira, Justin J. Lee, Matthias T. Wolf, R. Todd Alexander, and Henrik Dimke. "Gentamicin Inhibits Ca²⁺ Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor–Claudin-14 Pathway." Journal of the American Society of Nephrology 33, no. 3 (January 12, 2022): 547–64. http://dx.doi.org/10.1681/asn.2021030392.

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BackgroundTreatment with the aminoglycoside antibiotic gentamicin can be associated with severe adverse effects, including renal Ca2+ wasting. The underlying mechanism is unknown but it has been proposed to involve activation of the Ca2+-sensing receptor (CaSR) in the thick ascending limb, which would increase expression of claudin-14 (CLDN14) and limit Ca2+ reabsorption. However, no direct evidence for this hypothesis has been presented.MethodsWe studied the effect of gentamicin in vivo using mouse models with impaired Ca2+ reabsorption in the proximal tubule and the thick ascending limb. We used a Cldn14 promoter luciferase reporter assay to study CaSR activation and investigated the effect of gentamicin on activity of the distal nephron Ca2+ channel transient receptor potential vanilloid 5 (TRPV5), as determined by patch clamp in HEK293 cells.ResultsGentamicin increased urinary Ca2+ excretion in wild-type mice after acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and was present in furosemide-treated animals, whereas the calciuretic effect in Cldn14−/− mice and mice with impaired proximal tubular Ca2+ reabsorption (claudin-2 [CLDN2]-deficient Cldn2−/− mice) was equivalent to that of wild-type mice. In vitro, gentamicin failed to activate the CaSR. In contrast, patch clamp analysis revealed that gentamicin strongly inhibited rabbit and human TRPV5 activity and chronic gentamicin administration downregulated distal nephron Ca2+ transporters.ConclusionsGentamicin does not cause hypercalciuria via activation of the CaSR-CLDN14 pathway or by interfering with proximal tubular CLDN2-dependent Ca2+ reabsorption. Instead, gentamicin blocks distal Ca2+ reabsorption by direct inhibition of the Ca2+ channel TRPV5. These findings offer new insights into Ca2+ wasting in patients treated with gentamicin.

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Rahman, Abidur, Makoto Kobayashi, Kotaro Sugimoto, Yuta Endo, Manabu Kojima, Shigenori Furukawa, Takafumi Watanabe, et al. "Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer." International Journal of Molecular Sciences 22, no. 7 (April 6, 2021): 3774. http://dx.doi.org/10.3390/ijms22073774.

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Background: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. Methods: We generated a monoclonal Ab (mAb) against human/mouse CLDN12 and verified its specificity. By performing immunohistochemical staining and semiquantification, we evaluated the relationship between CLDN12 expression and clinicopathological parameters in tissues from 138 cases of cervical cancer. Results: Western blot and immunohistochemical analyses revealed that the established mAb selectively recognized the CLDN12 protein. Twenty six of the 138 cases (18.8%) showed low CLDN12 expression, and the disease-specific survival (DSS) and recurrence-free survival rates were significantly decreased compared with those in the high CLDN12 expression group. We also demonstrated, via univariable and multivariable analyses, that the low CLDN12 expression represents a significant prognostic factor for the DSS of cervical cancer patients (HR 3.412, p = 0.002 and HR 2.615, p = 0.029, respectively). Conclusions: It can be concluded that a reduced CLDN12 expression predicts a poor outcome for cervical cancer. The novel anti-CLDN12 mAb could be a valuable tool to evaluate the biological relevance of the CLDN12 expression in diverse cancer types and other diseases.

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Journal articles on the topic 'CLDN16'

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