Abstract: TH-PO194
Conditional Genetic Disruption of Podocyte Cell-Specific Npr1 Provokes Kidney Dysfunction in Male and Female Mutant Mice in a Sex-Dependent Manner
Session Information
- Hypertension and CVD: Basic Research Findings
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Ramasamy, Chandramohan, Tulane University School of Medicine, New Orleans, Louisiana, United States
- Pandey, Kailash Nath, Tulane University School of Medicine, New Orleans, Louisiana, United States
Background
Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones that induce diuresis, natriuresis, and vasorelaxation and reduce blood pressure (BP) and blood volume homeostasis via activation of transmembrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPR-A) with increased accumulation of intracellular cGMP. The role of ANP/NPRA/cGMP signaling in podocytes, which are highly specialized epithelial cells covering the outer surfaces of renal glomerular capillaries, is not well understood.
Methods
In this study, we determined the impact of conditional gene-knockout (KO) of podocyte (PD)-specific Npr1 (encoding NPRA) in male and female mice. Tamoxifen-treated wild-type control (PD Npr1 f/f; WT), heterozygous (PD-Cre-Npr1 f/+; HT), and gene-knockout (PD-Cre-Npr1 f/-; KO) mice were fed a normal-, low-, or high-salt diet for 28 days. Podocytes isolated from KO male and female mice exhibited a complete absence of Npr1 mRNA and NPRA protein levels compared with WT mice.
Results
On a normal-salt diet, mean arterial pressure (MAP) and heart rate (HR) were significantly higher (p<0.05; p<0.01; p<0.001) in both male and female PD-Npr1 KO mice compared with WT mice at 2, 4, 6, 8, and 12 weeks as measured by radiotelemetry. On a high-salt diet, the systolic blood pressure (SBP) was significantly (p<0.01; p<0.001) higher in the PD-Npr1 HT mice (male:109.50 ± 1.20; female: 102.30 ± 0.60) and KO mice (male:116.20 ± 1.1; female: 104.40 ± 1.20) compared with WT mice (male: 96.30 ± 0.70; female: 92.60 ± 0.60) after 28 days as measured by computerized tail-cuff method. On normal-, low-, and high-salt diets, plasma sodium, and albumin/creatinine ratio were significantly (p<0.05; p<0.01; p<0.001) increased, while creatinine clearance and urinary sodium levels were significantly (p<0.05; p<0.01; p<0.001) reduced in the HT and KO male and female mice compared to WT mice. These changes were significantly greater in males than females. Immunofluorescence of podocin and synaptopodin were also significantly (p<0.01; p<0.001) reduced in HT and KO mice compared to WT mice.
Conclusion
These observations suggest that in podocytes, ANP/NPRA/cGMP signaling may be crucial in the maintenance and regulation of BP and GFR suggesting as a biomarker of renal function in a sex-dependent manner.
Funding
- NIDDK Support