Identification of an Electrogenic 2Cl−/H+ Exchanger, ClC5, as a Chloride-Secreting Transporter Candidate in Kidney Cyst Epithelium in Tuberous Sclerosis

Abstract

Kidney cyst expansion in tuberous sclerosis complex (TSC) or polycystic kidney disease (PKD) requires active secretion of chloride (Cl-) into the cyst lumen. In PKD, Cl- secretion is primarily mediated via the cystic fibrosis transmembrane conductance regulator in principal cells. Kidney cystogenesis in TSC is predominantly composed of type A intercalated cells, which do not exhibit noticeable expression of cystic fibrosis transmembrane conductance regulator. The identity of the Cl--secreting molecule(s) in TSC cyst epithelia remains speculative. Based on RNA-sequencing analysis studies, we examined the expression of FOXi1, the chief regulator of acid base transporters in intercalated cells, along with localization of Cl- channel 5 (ClC-5), in kidneys of various models of TSC. Our results in Tsc2+/- mice show that the expansion of kidney cysts corresponds to the induction of Foxi1 and correlates with the strong appearance of ClC-5 and H+-ATPase on the apical membrane of cyst epithelia. In various mouse models of TSC, Foxi1 is robustly induced in the kidney, and ClC-5 appears along with H+-ATPase on the apical membrane of cyst epithelia. Expression of ClC-5 was also detected on the apical membrane of cyst epithelia in humans with TSC but was absent in humans with autosomal dominant PKD or in a mouse model of PKD. These results indicate that ClC-5 is expressed on the apical membrane of cyst epithelia and is a likely candidate mediating Cl- secretion into the kidney cyst lumen in TSC.