Renal tubule cell-specific deletion of Npr1 in mice led to significantly higher systolic blood pressure (e.g., male KO 132 vs WT 105 mmHg) and reduced GFR, with more pronounced changes in males.
Does renal tubule cell-specific deletion of Npr1 increase blood pressure and cause renal dysfunction in mice?
Loss of Npr1 in renal tubules leads to arterial hypertension and abnormal renal functional changes, which are more pronounced in male mice.
valor p: p=<0.01
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 renal tubules (RTs) often results in nephron dysfunction, leading to renal failure and elevated BP. The objective of the present study was to investigate the consequences of RT cell-specific deletion of Npr1 (encoding NPRA) on BP and renal sodium homeostasis. Doxycycline-treated RT cell-specific Npr1 knockout (KO; Npr1 f/-), heterozygous (HT; Npr1 f/+), and wild-type (WT; Npr1 f/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 RT-Npr1 KO mice did not express Npr1 mRNA or NPRA protein. Loss of Npr1 in RT 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 on a normal salt diet, 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 RT-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) at 28 days in a sex-specific manner. On a normal-salt diet, GFR was significantly (p< 0.05; p< 0.01; p< 0.001) reduced in RT-Npr1 KO (male: male: 51%, female: 42%) and RT-Npr1 HT (male: male: 28%, female: 18%) as compared with compared to WT mice. On normal-, low-, and high-salt diets, plasma creatinine and urinary protein were significantly increased, while plasma total protein and albumin were significantly reduced (p< 0.05; p< 0.01; p< 0.001) in the RT-Npr1 KO and HT male and female mice compared to WT mice. These changes were significantly greater in males than in females. Histological analysis confirmed greater progression of renal pathologies, including tubulointerstitial fibrosis and inflammatory infiltrates, in RT-Npr1 KO and HT male mice than in female KO and HT mice compared to WT mice. This is the first report to show that loss of Npr1 along the nephron leads to arterial hypertension and abnormal renal functional hemodynamic changes in a sex-specific manner. Our findings indicate that these abnormal renal functional changes are more pronounced in male mice compared to female mice. This work is supported by an NIH/NIDDK grant (DK133833). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Neelamegam et al. (Fri,) conducted a other in Hypertension and renal dysfunction. Renal tubule cell-specific deletion of Npr1 vs. Wild-type mice was evaluated on Blood pressure and renal sodium homeostasis (p=<0.01). Renal tubule cell-specific deletion of Npr1 in mice led to significantly higher systolic blood pressure (e.g., male KO 132 vs WT 105 mmHg) and reduced GFR, with more pronounced changes in males.
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