Abstract 4362278: Ablation of Nephron Tubule Cell-Specific <i>Npr1</i> Triggers High Blood Pressure and Dysfunction

Introduction: Cardiac hormone, atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) and regulate intravascular fluid volume and electrolyte homeostasis. Damage to nephron tubules (NTs) often results in renal malfunction, leading to high blood pressure (BP). To investigate the consequences of NT cell-specific deletion of Npr1 (encoding GC-A/NPRA) on BP and 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. Methods: The proximal tubule (PT), distal tubule (DT), and cortical collecting duct (CCD) were isolated from NT- Npr1 KO mice and did not express Npr1 mRNA or receptor protein. Mean arterial pressure (MAP) and heart rate (HR) were measured by radiotelemetry method and systolic blood pressure (SBP) was measured by non-invasive computerized tail-cuff method (Visitech 2000). Results: Loss of Npr1 in NT segments significantly (p&lt;0.01; p&lt;0.001) increased MAP and HR in both male and female mice compared to WT mice, as measured by the radiotelemetry method. On a high-salt diet, the SBP was significantly higher (p&lt;0.01; p&lt;0.001) in the NT- Npr1 KO male mice (132 ± 5 mmHg) and female mice (125 ± 4 mmHg) and also in HT male mice (118 ± 4 mmHg) and female mice (107 ± 3 mmHg) compared with WT male (105 ± 4 mmHg) and female (99 ± 3 mmHg) mice in a sex-specific manner. Plasma creatinine and urinary protein were significantly increased (p&lt;0.05; p&lt;0.01; p&lt;0.001), while plasma total protein and albumin were also significantly reduced (p&lt;0.05; p&lt;0.01; p&lt;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. Glomerular filtration rate (GFR) was significantly (p&lt;0.05; p&lt;0.01; p&lt;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. Conclusion: Our results show that loss of Npr1 along the nephron segments leads to arterial hypertension and abnormal renal hemodynamic changes. Supported by NIH/NIDDK grant (DK133833).