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

Abstract

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. Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the <i>Ift88</i> 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). 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. Nephron cilia disruption in male, but not female, mice (<i>1</i>) reduces BP prior to cyst formation, (<i>2</i>) increases NOx production that may account for the lower BP prior to cyst formation, and (<i>3</i>) induces polycystic kidneys that are associated with hypertension and reduced renal NO production.