Deletion of claudin-10 rescues claudin-16–deficient mice from hypomagnesemia and hypercalciuria

Abstract

The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin.

Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney

“…Studies in mouse and human suggest that there are structural and functional differences between medullary and cortical TAL driven by regional expression patterns of claudins 47,48 . Claudin-10 and claudin-16 regulate paracellular reabsorption of calcium and magnesium in the thick ascending limb.…”

“…In contrast, targeted deletion of Cldn10 in the thick ascending limb results in impaired paracellular sodium permeability and hypermagnesemia 47 . Interestingly, Cldn10 deletion can partially rescue the phenotype of Cldn16-deficient mice (double knockout) 48 . These data suggest that Cldn10 and Cldn16 have opposing effects on cation reabsorption in the thick ascending limb and are supported by the observation that Cldn10 and Cldn16 are expressed in a mosaic pattern in mice 66 .…”

“…Pathogenic germline variants in CLDN16 are causative of familial hypomagnesemia, hypercalciuria and nephrocalcinosis, which can lead to end-stage renal disease 45,46 . Interestingly, Cldn10 deletion causes hypermagnesemia in mice 47 , and even rescues Cldn16deficient mice from hypomagnesemia and hypercalciuria 48 . These data indicate that CLDN10 and CLDN16 may confer opposing segment-specific tight junction cation selectivity.…”

Inching toward a Greater Understanding of Genetic Hypercalciuria

“…Much of the bulk reabsorption at these sites is paracellular rather than transcellular (3). Proximal tubular calcium reabsorption does not seem to be regulated, and it is thought to largely occur as a part of bulk paracellular ion and water flows (5,7). The specifics of calcium reabsorption in the thick limb (6) are more complicated (Figure 1).…”

“…The remaining 10% of filtered calcium is reabsorbed transcellularly in the distal nephron via apical calcium channels (TRPV5), intracellular calbindin-28K, a basolateral sodium-calcium exchanger (NCX1), and calcium-ATPase (PMCA1b) (6). Calcium reabsorption in the distal nephron is against an electrochemical gradient under the combined regulation of parathyroid hormone and 1,25-vitamin D, which in turn, are ultimately responsive to peripheral ionized blood calcium concentrations (6,7).…”