Abstract Body: Atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) and regulate blood pressure (BP), intravascular volume, and electrolyte homeostasis. Injury to nephron tubules (NTs) often results in nephron malfunction, leading to loss of renal function and higher BP. To investigate the sex-specific consequences of NT cell-specific deletion of Npr1 (encoding NPRA) on BP and renal sodium homeostasis, doxycycline-treated NT cell-specific Npr1 knockout (KO; Npr1 f/-), heterozygous (HT; Npr1 f/+), and wild-type (WT; Npr1 f/f) male and female mice were used. 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. 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. On a high-salt diet, 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) in a sex-specific manner. Plasma creatinine and urinary protein were significantly increased (p<0.05; p<0.01; p<0.001), while plasma total protein and albumin were also 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. 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. Using histological analysis, we confirmed the progression of renal pathologies, including tubulointerstitial fibrosis and interstitial inflammatory infiltrate in NT-Npr1 KO and NT-Npr1 HT male and female mice compared with NT-Npr1 WT mice. In conclusion, the results show that loss of Npr1 along the nephron segments leads to arterial hypertension and abnormal renal functional hemodynamic changes. Further, our findings indicate that these abnormal renal functional changes are more pronounced in male mice compared to female mice. Supported by NIH/NIDDK grant (DK133833).