Renal Tubule Cell-Specific Npr1 is Essential to Regulate Blood Pressure and Kidney Dysfunction

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Abstract
BACKGROUND: Atrial and brain natriuretic peptides activate GC-A/NPRA (guanylyl cyclase-A/natriuretic peptide receptor-A) and regulate blood pressure and electrolyte homeostasis. Renal tubule (RT) dysfunction results in decreased kidney function and increased blood pressure. We determined the sex-specific consequences of RT cell-specific deletion of Npr1 (encoding NPRA) on blood pressure and renal hemodynamics. METHODS: Mice were generated with inducible RT knockout by breeding lox-flanked (flox/flox: f/f ) exons 1 to 2 in Npr1 with mice expressing the Pax8-rtTA-LC-1- Cre transgene. Doxycycline-treated RT cell-specific Npr1 knockout ( Npr1 f/ −), heterozygous (HT; Npr1 f/+ ), and wild-type ( Npr1 f/f ) male and female mice were used. Proximal tubule, distal tubule, and cortical collecting duct were isolated from RT- Npr1 knockout mice and did not express Npr1 mRNA or protein. RESULTS: RT cell-specific male knockout and HT mice showed significantly lower glomerular filtration rate, creatinine clearance, and urinary sodium excretion than female mice, compared with wild-type mice. The effect of Npr1 deletion was more severe on high-salt diets than their normal-diet counterparts. Loss of Npr1 in RT segments significantly increased systolic blood pressure and mean arterial pressure in a sex-specific manner. Mutant male mice showed higher total urinary protein and albumin-creatinine ratios than female mice. On a high-salt diet, male knockout and HT mice showed greater salt sensitivity than female mice. CONCLUSIONS: Loss of Npr1 along the nephron tubules leads to arterial hypertension and abnormal renal functional hemodynamic changes that are more pronounced in male mice compared with female mice.

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