Claudins and the Kidney

Journal of the American Society of Nephrology

Hou

2014

Self Cite

109

Pathologic dysregulation of extracellular calcium metabolism is difficult to correct. The extracellular Ca ++ -sensing receptor (CaSR), a G protein-coupled receptor that regulates renal Ca ++ handling through changes in paracellular channel permeability in the thick ascending limb, has emerged as an effective pharmacological candidate for managing calcium metabolism. However, manipulation of CaSR at the systemic level causes promiscuous effects in the parathyroid glands, kidneys, and other tissues, and the mechanisms by which CaSR regulates paracellular transport in the kidney remain unknown. Here, we describe a CaSR-NFATc1-microRNAclaudin-14 signaling pathway in the kidney that underlies paracellular Ca ++ reabsorption through the tight junction. With CaSR-specific pharmacological reagents, we show that the in vivo gene expression of claudin-14 is regulated through a transcriptional mechanism mediated by NFATc1-microRNA and associated chromatin remodeling. Transgenic knockout and overexpression approaches showed that claudin-14 is required for CaSR-regulated renal Ca ++ metabolism. Together, our results define an important signaling cascade that, when dysregulated, may mediate Ca ++ imbalance through changes in tight junction permeability.

Section: Discussionmentioning

confidence: 99%

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

Journal of the American Society of Nephrology

Hou

2014

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109

“…The predominant Ca ++ reabsorption sites are in the PT, the TALH, and the DCT. 11,12 Although the PT and TALH use the paracellular pathway to handle Ca ++ , 11 the DCT relies on a coordinated transcellular Ca ++ transport pathway based on the apically localized transient receptor potential channel V member 5 (TRPV5) and the basolaterally localized Na + /Ca ++ exchanger 1 (NCX1). 12 Because HDAC is a global regulator of gene expression, its renal effects could stem from different tubular segments.…”

mentioning

confidence: 99%

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

Journal of the American Society of Nephrology

Himmerkus

Plain

et al. 2015

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The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney-claudin-14, -16, and -19-as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases.

“…The claudins are a 28-member family of tetraspan proteins that range in molecular mass from 20 to 28 kDa and form a class of ion channels oriented perpendicular to the membrane plane and connecting two extracellular compartments, known as the paracellular channel (13). Claudins associate by cis interactions within the plasma membrane of the same cell followed by trans interactions between neighboring cells to assemble them in the TJ.…”

mentioning

confidence: 99%

The Cap1–claudin-4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation

Proc. Natl. Acad. Sci. U.S.A.

Yang³

et al. 2014

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The paracellular pathway through the tight junction provides an important route for transepithelial chloride reabsorption in the kidney, which regulates extracellular salt content and blood pressure. Defects in paracellular chloride reabsorption may in theory cause deregulation of blood pressure. However, there is no evidence to prove this theory or to demonstrate the in vivo role of the paracellular pathway in renal chloride handling. Here, using a tissue-specific KO approach, we have revealed a chloride transport pathway in the kidney that requires the tight junction molecule claudin-4. The collecting duct-specific claudin-4 KO animals developed hypotension, hypochloremia, and metabolic alkalosis due to profound renal wasting of chloride. The claudin-4-mediated chloride conductance can be regulated endogenously by a proteasechannel-activating protease 1 (cap1). Mechanistically, cap1 regulates claudin-4 intercellular interaction and membrane stability. A putative cap1 cleavage site has been identified in the second extracellular loop of claudin-4, mutation of which abolished its regulation by cap1. The cap1 effects on paracellular chloride permeation can be extended to other proteases such as trypsin, suggesting a general mechanism may also exist for proteases to regulate the tight junction permeabilities. Together, we have discovered a theory that paracellular chloride permeability is physiologically regulated and essential to renal salt homeostasis and blood pressure control.chloride channel | epithelium | hypertension C hloride is the most abundant extracellular anion and thereby determines extracellular fluid volume (ECFV) and blood pressure (BP) (1, 2). The kidney plays a vital role in ECFV and BP control through complex regulatory mechanisms acting upon ion channels and transporters located in the aldosterone-sensitive distal nephron (ASDN) (3, 4). The ASDN comprises the distal convoluted tubule (DCT), the connecting tubule (CNT), and the collecting duct (CD). The primary chloride transport mechanism in the DCT is through the thiazide-sensitive Na + /Cl − cotransporter (NCC) to reabsorb Cl − coupled with equal moles of Na + (5). The chloride transport mechanism in the CNT and CD, on the other hand, has been under debate for many years. Recent advances have identified an electroneutral transport pathway for chloride using the Cl − /bicarbonate exchanger (Slc26a4; pendrin) (6) and the Na + -driven Cl − /bicarbonate exchanger (Slc4a8; NDCBE) (7) in the β-intercalated cells (ICs) of CNT and CD. However, such an electroneutral pathway is not able to couple Cl − reabsorption with epithelial sodium channel (ENaC)-based Na + reabsorption that takes place in the principal cells (PCs) of CNT and CD (8), despite many efforts to connect ENaC and pendrin gene expression through endocrine or paracrine mechanisms (9, 10). We and others have previously demonstrated the presence of a paracellular Cl − pathway or "chloride shunt" in vitro in the CNT and CD cells (11,12). The paracellular Cl − channel is made of a key claud...