Deletions of Npr1 in Nephron Tubule Cells Lead to Salt-Sensitive Hypertension and Kidney Dysfunction in Both Male and Female Mutant Mice

Background: Binding of atrial and brain natriuretic peptides (ANP and BNP) to guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) generates the second messenger cGMP, regulating blood pressure (BP), intravascular volume, and electrolyte homeostasis. Nephron tubules (NTs) injury often results in nephron malfunction, leading to loss of kidney function and higher BP. Methods: To investigate the consequences of NT cell-specific deletion of Npr1 (encoding NPRA) on BP and renal sodium homeostasis, doxycycline-treated NT cell-specific Npr1 knockout (KO; Npr1f/-), heterozygous (HT; Npr1f/+), and wild-type (WT; Npr1f/f) male and female mice were fed a normal-, low-, or high-salt diet for 28 days. Proximal tubule (PT), distal tubule (DT), and cortical collecting duct (CCD), isolated from NT- Npr1 KO mice did not express Npr1 mRNA or NPRA protein. Results: Loss of Npr1 in NT segments significantly (p<0.01; p<0.001) increased mean arterial pressure (MAP) and heart rate (HR) in both male and female mice compared to WT mice, as measured by the radiotelemetry method. The systolic blood pressure (SBP) was significantly higher (p<0.01; p<0.001) in the NT-Npr1 KO mice (male: 132 ± 5 mmHg; female: 125 ± 4 mmHg)) and HT mice (male: 118 ± 4 mmHg; female: 107 ± 3 mmHg) compared with WT mice (male: 105 ± 4 mmHg; female: 99 ± 3 mmHg). GFR was significantly (p<0.05; p<0.01; p<0.001) reduced in NT-Npr1 KO (male: male: 51%, female: 42%) and NT-Npr1 HT (male: male: 28%, female: 18%) as compared with WT mice. On normal-, low-, and high-salt diets, plasma creatinine and urinary protein were significantly increased (p<0.05; p<0.01; p<0.001), while plasma total protein and albumin were significantly reduced (p<0.05; p<0.01; p<0.001) in the NT-Npr1 KO and HT male and female mice compared to WT mice. These changes were significantly greater in males than females. Histological analysis, including tubulointerstitial fibrosis and interstitial inflammatory infiltrate were more pronounced in NT-Npr1 KO and NT-Npr1 HT male than female mice compared with NT-Npr1 WT mice. Conclusion: In summary the results show that loss of Npr1 along the nephron leads to arterial hypertension and abnormal renal functional hemodynamic changes in a sex-specific manner, which are more pronounced in male mice compared to female mice. Funding: NIDDK Support