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

Abstract Sexual dimorphism profoundly influences physiology, disease susceptibility, and therapeutic responses, yet its effects on kidney mitochondrial function remain unclear. We hypothesized that sex differences in kidney mitochondrial function would parallel those in other organs, with females exhibiting greater oxidative capacity and lower oxidative stress. To test this, we measured oxidative phosphorylation (OXPHOS) kinetics and hydrogen peroxide (H2O2) emission in cortical and outer medullary (OM) mitochondria isolated from young male and female Dahl salt-sensitive (SS) rats maintained on a low-salt diet. Unexpectedly, 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 was accompanied by increased Complex IV protein abundance without changes in mitochondrial DNA copy number or dynamics markers. In the OM, both mitochondrial respiration and H2O2 emission exceeded cortical levels, but showed no sex differences. Analysis of kidney transporter protein abundance revealed a sex-specific “downstream shift” in nephron transport, with males exhibiting greater proximal tubule (PT) sodium reabsorption potential and reduced distal transport capacity. Elevated cortical OXPHOS activity in males likely supports these higher PT energy demands. Thus, sex differences in renal mitochondrial function diverge from other organs, reflecting kidney-specific energetic priorities that override systemic maternal inheritance and sex hormone influences. Enhanced cortical H2O2 emission in males may underlie their heightened susceptibility to kidney injury and salt sensitivity.