Claudins in barrier and transport function—the kidney

Abstract

Summary Claudins are discovered to be key players in renal epithelial physiology. They are involved in developmental, physiological and pathophysiological differentiation. In the glomerular podocytes, claudin-1 is an important determinant of cell junction fate. In the proximal tubule, claudin-2 plays important roles in paracellular salt reabsorption. In the thick ascending limb, claudin-14, -16 and -19 regulate the paracellular reabsorption of calcium and magnesium. Recessive mutations in claudin-16 or -19 cause an inherited calcium and magnesium losing disease. Synonymous variants in claudin-14 have been associated with hypercalciuric nephrolithiasis by genome wide association studies (GWAS). More importantly, claudin-14 gene expression can be regulated by extracellular calcium levels via the calcium sensing receptor. In the distal tubules, claudin-4 and -8 form paracellular chloride pathway to facilitate electrogenic sodium reabsorption. Aldosterone, WNK4, Cap1 and KLHL3 are powerful regulators of claudin and the paracellular chloride permeability. The lessons learned on claudins from the kidney will have a broader impact on tight junction biology in other epithelia and endothelia.

Alteration of Tight Junction Protein Expression in Dahl Salt-Sensitive Rat Kidney

“…Claudin-2 has a role in Na + reabsorption in the proximal tubule [10], but its expression was not associated with impaired natriuresis in our Dahl SS rats. On the other hand, the expression of claudin-4, recently reported to act as an important route for Cl – reabsorption in the collecting duct [27], was increased at both the protein and mRNA level in our animal model of SS hypertension. This finding is consistent with a previous study demonstrating that chloride contributes to the development and severity of hypertension in the Dahl SS rat [28].…”

“…Claudin-7 and -8 are also expressed in the collecting duct [27]. Although severe renal salt wasting and hypovolemia was induced by genetic ablation of claudin-7 in mice [29], it is not clear whether claudin-7 directly contributes to the paracellular chloride pathway [27].…”

The importance of the thick ascending limb of Henle’s loop in renal physiology and pathophysiology

“…19 Their role in divalent cations absorption has been recently highlighted by the discovery of salt losing phenotype associated with their dysfunction due to genetic mutations. 20 However, several evidences suggest that a significant component of Ca 2+ reabsorption occurs also via transcellular pathway. 21 The presence on the basolateral membrane of the Na + /Ca 2+ exchanger (NCX) and the Ca 2+ ATPase (PMCA) confirms the presence of a basolateral exit, and suggests the possible presence of a luminal route for Ca 2+ entry.…”

“…20 In mammals, over 24 claudin genes have been described; some genes exhibit peculiar tissue-specificity expression, others are expressed in several organs and tissues. In the kidney, several claudins have been mapped along the nephron.…”

“…73 Recessive mutations of CLDN16 and CLDN19 (encoding claudin-19) are the most common causes of FHHNC. 20 The disease is believed to be the result of a deficient reabsorption of divalent cations in the TAL due to a defective paracellular barrier. This defect results in increased fractional excretion of Ca 2+ and Mg…”