Renal mitochondrial metabolism is differentially regulated in male and female kidneys in Ang II -- induced hypertension

Abstract

Introduction. In 2020, more than 670,000 deaths in the United States had hypertension as a primary or contributing cause. Females generally exhibit less susceptibility to hypertensive renal damage compared to males. It is established that renal mitochondrial dysfunction and associated oxidative stress contribute to hypertension development. Our previous studies have shown that healthy renal mitochondria in the absence of hypertension exhibit sex differences in antioxidant protein abundance, ROS production, and oxygen consumption rates. We hypothesized here that in hypertensive state mitochondrial metabolism in male and female kidneys differentially regulates tissue damage and ultimately hypertension in females. Methods. To address our hypothesis, we used 11-week-old male and female Sprague Dawley rats infused with Angiotensin II (400 ng/kg/min to induce hypertension) or vehicle for 3 weeks via a s.c. osmotic pump. Mitochondria were isolated from the renal cortex and medulla of these rats; mitochondrial membrane potential and H 2 O 2 production were measured by spectrofluorimetry using TMRM and Amplex Red dyes. Two-way ANOVA was utilized for statistical analysis in OriginPro. Metabolic profiles of renal cortices and medullae were generated using UHPLC-HRMS, and metabolites were identified by retention time exact mass using MAVEN and MetaboAnalyst software. Results. Spectrofluorimetry showed decreased membrane potential in both male and female renal medulla in animals infused with Ang II compared to vehicle (p<0.001), while in cortex this difference was only recorded in females (p=0.03). Ang II-infusion reduced H 2 O 2 production in the renal cortex and medulla of female rats (p<0.001) compared to sham groups, while this was not observed in males. In both Ang II and vehicle-infused groups, females maintained higher H 2 O 2 production compared to males. UHPLC-HRMS identified 147 mitochondria-related metabolites in each group. Ang II infusion increased TCA cycle and purine metabolites as well as amino acids in the cortex of both sexes and in male medulla, whereas these changes were not revealed in the female medulla. Interestingly, females exhibited a decrease in amino acid metabolism in the renal medulla. In contrast to the male cortex, the female cortex is responding to oxidative stress induced by hypertension by altering arginine biosynthesis and metabolism. Arginine is a biosynthetic precursor to putrescine, which is involved in polyamine biosynthesis. Conclusions. Male and female kidneys employ divergent metabolic mitochondria-related pathways in hypertensive state. The male cortex may rely more on protein degradation to produce uric acid, an antioxidant, while the female cortex utilizes protein degradation and polyamine biosynthesis in oxidative stress management. R01HL148114 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.