Podocyte cell-specific <i>Npr1</i> is required for blood pressure and renal homeostasis in male and female mice: role of sex-specific differences

Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA), stimulating natriuresis and diuresis and reducing blood pressure (BP), but the role of ANP/NPRA signaling in podocytes (highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries) remains unclear. This study aimed to determine the effect of conditional deletion of podocyte-specific <i>Npr1</i> (encoding NPRA) gene knockout (KO) in male and female mice. Tamoxifen-treated wild-type control (PD <i>Npr1</i> f/f; WT), heterozygous (PD-Cre-<i>Npr1</i> f/+; HT), and KO (PD-Cre-<i>Npr1</i> f/-) mice were fed a normal-, low-, or high-salt diet for 4 wk. Podocytes isolated from HT and KO male and female mice showed complete absence of <i>Npr1</i> mRNA and NPRA protein compared with WT mice. BP, plasma creatinine, plasma sodium, urinary protein, and albumin/creatinine ratio were significantly increased, whereas plasma total protein, albumin, creatinine clearance, and urinary sodium levels were significantly reduced in the HT and KO male and female mice compared with WT mice. These changes were significantly greater in males than in females. On a normal-salt diet, glomerular filtration rate was significantly decreased in PD <i>Npr1</i> HT and KO male and female mice compared with WT mice. Immunofluorescence of podocin and synaptopodin was also significantly reduced in HT and KO mice compared with WT mice. These observations suggest that in podocytes, ANP/NPRA signaling may be crucial in the maintenance and regulation of glomerular filtration and BP and serve as a biomarker of renal function in a sex-dependent manner.<b>NEW & NOTEWORTHY</b> Our results demonstrate that the podocyte-specific deletion of <i>Npr1</i> showed increased blood pressure (BP) and altered biomarkers of renal functions, with greater magnitudes in animals fed a high-salt diet in a sex-dependent manner. The results suggest a direct and sex-dependent effect of <i>Npr1</i> ablation in podocytes on the regulation of BP and renal function and reveal that podocytes may be considered an important target for the ANP-BNP/NPRA/cGMP signaling cascade.