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

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.