Profiling renal sodium transporters in mice with nephron Ift88 disruption: Association with sex, cysts, and blood pressure.

Abstract

Loss of nephron primary cilia due to disruption of the Ift88 gene results in sex‐ and age‐specific phenotypes involving renal cystogenesis, blood pressure (BP) and urinary Na+ excretion. Previous studies demonstrated that male mice undergoing induction of nephron‐specific Ift88 gene disruption at 2 months of age developed reduced BP and increased salt‐induced natriuresis when pre‐cystic (2 months post‐induction) and became hypertensive associated with frankly cystic kidneys by 9 months post‐induction; in contrast, female Ift88 KO mice manifested no unique phenotype 2 months post‐induction and had mildly reduced BP 9 months post‐induction. The current study utilized these Ift88 KO mice to investigate associated changes in renal Na+ transporter and channel protein expression. At 2 months post‐induction, pre‐cystic male Ift88 KO mice had reduced high salt diet associated total NKCC2 levels while female mice had no alterations in Na+ transporters or channels. At 9 months post‐induction, cystic male Ift88 KO mice had increased total and phosphorylated NHE3 levels together with reduced NKCC2, phosphorylated and/or total NCC, and ENaC‐α expression on normal and high salt diets. In contrast, female Ift88 KO mice at 9 months post‐induction had no changes in Na+ transporters or channels beyond an increase in phosphorylated‐NCC during high salt intake. Thus, reduced BP in pre‐cystic, and elevated BP in renal cystic, male Ift88 KO mice are associated with unique sex‐dependent changes in nephron Na+ transporter/channel expression.