Deciphering the Claudins that Mediate Renal Calcium Reabsorption

Kidney stones and osteoporosis are prevalent clinical conditions posing a large economic burden to the healthcare system. A common risk factor for both these diseases is hypercalciuria, which is the inappropriate excretion of calcium in urine. Changes in serum calcium levels are detected by the calcium sensing receptor (CaSR). In the kidney, the CaSR is localized in tubular segments where calcium (Ca²⁺) flux occurs via the paracellular pathway, specifically the proximal tubule and the thick ascending limb of Henle’s loop (TAL). Claudins are proteins localized in the tight junction of epithelia that control paracellular ion flux. Recently, claudin-14 (Cldn14) expression was observed in the TAL. We found that Cldn14 is regulated by dietary Ca ²⁺ intake and by elevated serum Ca²⁺ levels after prolonged 1,25-dihydroxyvitamin D₃ administration in mice. Consistent with this, in vivo activation of the CaSR by administration of the calcimimetic Cinacalcet, lead to a 40-fold increase in Cldn14 mRNA abundance. Overexpression of Cldn14 in a renal tubular cell culture model inhibited paracellular Ca²⁺ flux. Together the data suggests that when serum Ca ²⁺ level increases it activates the CaSR leading to increased Cldn14 expression in the TAL. This in turn blocks Ca²⁺ reabsorption and induces calciuria. Dysregulation of this newly described CaSR-Cldn14 axis likely contributes to the development of hypercalciuria and kidney stones.