Hypertension-Induced Kidney Damage: Role of Acid-Sensing Ion Channel 1a in Structural and Functional Changes

In the United States, nearly half of adults have systemic hypertension (defined as 130/80 mmHg), which is a major risk factor for heart disease and stroke. The kidneys play a critical role in blood pressure regulation, and often, hypertension and kidney disease coexist, worsening disease progression. Interestingly, we recently demonstrated that genetic deletion of acid-sensing ion channel 1a (ASIC1a) causes age-induced hypertension in male but not female mice. We hypothesize that hypertension is associated with structural and functional damage in the kidneys. To determine structural changes, we examined glomeruli cross-sectional area (CSA), number, and renal fibrosis young adult (~6 mo.) and aged (18 mo.) wild-type ( Asic1a +/+ ) and Asic1a knockout ( Asic1a -/- ) male and female mice. In male mice, aging significantly increased glomeruli CSA (p < 0.0001) and renal fibrosis (p < 0.0001) in both genotypes, but hypertensive aged Asic1a -/- mice exhibited a further increase in glomeruli CSA (p = 0.0014) and fibrosis (p < 0.0001), which was associated with a decrease in number of glomeruli (p=0.0009). Aged female Asic1a +/+ , but not Asic1a -/- , mice have elevated blood pressure and fewer glomeruli (p = 0.0080). While glomeruli CSA (p < 0.0001) and renal fibrosis (p = 0.0348) are increased with age in both groups, there is no significant difference between genotypes. These findings suggest that hypertension is associated with structural changes in the glomeruli and increased fibrosis. To investigate whether these structural changes impair kidney function, we measured urine protein, osmolality, and blood urea nitrogen (BUN). In male mice, urine osmolality was lower in both young (p < 0.0001) and aged (p = 0.0024) Asic1a -/- compared to Asic1a +/+ mice. While urine protein levels were higher in aged mice (p = 0.0001), neither urine protein nor BUN were affected by genotype. Although the structural changes in glomeruli are associate with hypertension, they do not cause overt kidney dysfunction. The reduced urine osmolality in male Asic1a -/- mice is independent of hypertension and suggests some early kidney dysfunction following ASIC1a deletion, which we plan to investigate further. This work was supported by R01HL111084 (Jernigan NL) and R25GM075149 (Miller K) This abstract was presented at the American Physiology Summit 2025 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.