Sex Differences in Renal Mitochondrial Respiration and H2O2 Emission in Young Dahl Salt-Sensitive Rats.

Abstract

Sexual dimorphism has a significant influence on physiology, disease susceptibility, and therapeutic responses, yet its impact on kidney mitochondrial function remains poorly understood. We hypothesized that sex differences in kidney mitochondrial function would parallel those observed in other organs, where females often exhibit higher oxidative capacity and lower oxidative stress. To test this, we measured the kinetics of oxidative phosphorylation (OXPHOS) and hydrogen peroxide (H2O2) emission in isolated cortical and outer medullary (OM) mitochondria from young male and female Dahl salt-sensitive (SS) rats fed a low-salt diet. Contrary to our hypothesis, male cortical mitochondria showed significantly higher O2 consumption during ATP synthesis (OXPHOS) than females when fueled by either complex I- or complex II-linked substrates. Cortical H2O2 emission was also greater in males, under both forward and reverse electron transport fueled by succinate. This difference was consistent with an increase in Complex IV protein abundance despite no changes in mitochondrial DNA copy number or markers of mitochondrial dynamics. In the OM, both mitochondrial respiration and H2O2 emission were higher than in the cortex, but no sex differences were observed. Analysis of kidney transporter protein abundance revealed a sex-specific "downstream shift" in nephron transport function. Males showed a greater sodium reabsorption potential in the proximal tubules (PT) and reduced capacity in distal segments. The elevated cortical OXPHOS activity in males likely supports these higher PT transport demands. These results indicate that sex differences in renal mitochondrial function diverge from those in other organs, suggesting that kidney-specific energetic demands override systemic maternal inheritance and sex hormone effects. The higher cortical H2O2 emission in males may contribute to a greater susceptibility to kidney injury and salt sensitivity.