Sex-Dependent Effects of Nephron Ift88 Disruption on BP, Renal Function, and Cystogenesis

Significance Statement Primary cilia regulation of renal function and BP is incompletely understood. Mice with inducible nephron-specific Ift88 (a key ciliary protein) knockout (KO) were developed. Two months post-KO, males had reduced BP, increased natriuresis, and increased renal nitric oxide (NO) production; female KO mice had no phenotype unique from control mice. Nine months post-KO, males had cystic kidneys, hypertension, and reduced urinary NO excretion; female Ift88 KO mice had reduced BP and rare cysts. These findings indicate that nephron cilia disruption causes (1) strongly sex-dependent cystogenesis, (2) sex-dependent early BP reduction associated with eventual cyst formation, and (3) altered renal NO production. Background Primary cilia regulation of renal function and BP in health and disease is incompletely understood. This study investigated the effect of nephron ciliary loss on renal physiology, BP, and ensuing cystogenesis. Methods Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the Ift88 gene at 2 months of age using a Cre-LoxP strategy. BP, kidney function, and renal pathology were studied 2 and 9 months after DOX (Ift88 KO) or vehicle (control). Results At 2 months post-DOX, male, but not female, Ift88 KO, compared with sex-matched control, mice had reduced BP, enhanced salt-induced natriuresis, increased urinary nitrite and nitrate (NOx) excretion, and increased kidney NOS3 levels, which localized to the outer medulla; the reductions in BP in male mice were prevented by L-NAME. At 9 months post-DOX, male, but not female, Ift88 KO mice had polycystic kidneys, elevated BP, and reduced urinary NOx excretion. No differences were observed in plasma renin concentration, plasma aldosterone, urine vasopressin, or urine PGE2 between Ift88 KO and control mice at 2 or 9 months post-DOX. Conclusions Nephron cilia disruption in male, but not female, mice (1) reduces BP prior to cyst formation, (2) increases NOx production that may account for the lower BP prior to cyst formation, and (3) induces polycystic kidneys that are associated with hypertension and reduced renal NO production.