Claudin-19 localizes to the thick ascending limb where its expression is required for junctional claudin-16 localization

The kidney is critical for mineral homeostasis. Calcium and magnesium reabsorption in the renal thick ascending limb (TAL) involves claudin-16 (CLDN16) and claudin-19 (CLDN19) and pathogenic variants in either gene lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe calcium and magnesium wasting. While both CLDN16 and CLDN19 localize to the TAL, varying expression patterns in the renal tubule have been reported using different antibodies. We, therefore, studied the localization of CLDN19 in the kidneys of wild-type and Cldn19-deleted mice using three anti-CLDN19 antibodies and examined the role of Cldn19 deletion on CLDN16 and CLDN10 localization. We find that CLDN19 localizes to basolateral membrane domains of the medullary and cortical TAL but only to the tight junction of TALs in the outer stripe of outer medulla and cortex, where it colocalizes with CLDN16. Furthermore, in TALs from Cldn19-deleted mice, CLDN16 is expressed in basolateral membrane domains but not at the tight junction. In contrast, Cldn19 ablation does not change CLDN10 localization. These findings directly implicate CLDN19 in regulating permeability in the TAL by allowing junctional insertion of CLDN16 and may explain the shared renal phenotypic characteristics in FHHNC patients.

Automated summary

The kidney plays a critical role in maintaining mineral balance in the body. Dysregulation of calcium and magnesium reabsorption in the renal tubules can lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), which is characterized by excessive wasting of calcium and magnesium. This study investigated the localization of claudin-19 (CLDN19), a protein involved in mineral reabsorption, in the kidneys and found that it is primarily located in the basolateral membrane of the renal tubules. Additionally, the study showed that CLDN19 interacts with claudin-16 (CLDN16) to regulate permeability in the tubules. These findings provide insights into the pathophysiology of FHHNC and highlight the importance of CLDN19 in maintaining mineral homeostasis in the kidney.