Aging Female Offspring Exposed to Maternal Hyperandrogenemia have Increased Renal Mitochondrial Content and Decreased Mitochondrial Reactive Oxygen Species

Abstract

BackgroundPolycystic ovary syndrome (PCOS), the most common endocrine disorder in women, is characterized by hyperandrogenemia and elevated blood pressure. PCOS women who get pregnant have offspring with intrauterine growth restriction (IUGR). We use a clinically‐relevant rat model of PCOS, the hyperandrogenemic females (HAF), which develop most of the features of PCOS. Offspring of HAF dams are born with IUGR. We have previously shown that aging female HAF offspring are normotensive and are protected against angiotensin (Ang) II‐induced hypertension (HT). HT and Ang II‐induced HT have been shown to be associated with mitochondrial dysfunction. This study was performed to explore the renal mitochondrial function in aging female HAF offspring as a potential protective mechanism against Ang II HT.MethodsFemale Sprague Dawley rats were implanted with either 5α‐dihydrotestosterone (DHT; 7.5 mg/90 d, s.c.; HAF) or placebo pellets starting at 4 wks of age. HAF and controls were mated and allowed to deliver and lactate. Litters were culled to 4 males and 4 females on postnatal day 2. Female offspring were allowed to age to 16‐18 mos with no treatments, then euthanized and kidneys were collected for mitochondrial isolations (n = 3‐4, 1 rat/litter). Mitochondrial respiration and reactive oxygen species (mtROS) production were measured simultaneously by an Oroboros Fluorespirometer using glutamate/malate, succinate, oleate (long‐chain fatty acid; LCFA), or octanoate (medium chain fatty acid; MCFA). Complex IV activity, a marker of oxidative phosphorylation capacity, was measured by respirometry. Data were normalized to mitochondrial content using citrate synthase (CS) activity.ResultsDespite similar renal complex I and II‐driven respiration, renal LCFA (517 ± 24 vs 353 ± 34 nmol e‐/min/mg protein, p < 0.05) and MCFA (783 ± 58 vs 593 ± 58 nmol e‐/min/mg protein, p < 0.05) oxidation were significantly higher in HAF vs control offspring, respectively. Renal CS activity was significantly higher in HAF vs control offspring (884 ± 93 vs 616 ± 62 nmol/min/mg protein, respectively, p < 0.05). After normalization to CS activity, renal complex I and II‐driven respiration, LCFA and MCFA oxidation were similar between HAF and control offspring. Importantly, renal LCFA‐mediated ROS (4x10‐4 ± 7x10‐5 vs 8x10‐4 ± 2x10‐4 nmol e‐/CS activity, p < 0.05) and MCFA‐mediated ROS (6x10‐4 ± 10‐4 vs 10‐3± 2x10‐4 nmol e‐/CS activity, p < 0.05) production were lower in HAF vs control offspring, respectively. Renal complex I and II‐mediated ROS production and complex IV activity were similar between HAF and control offspring.ConclusionAging female HAF offspring have increased renal mitochondrial LCFA and MCFA oxidation that is due to increased mitochondrial content. They also have decreased mtROS production indicating a protection against renal mitochondria‐mediated oxidative stress compared to controls. Further studies are needed to determine if these differences have a mechanistic link to the protection against Ang II HT and whether there are changes in renal mitochondrial function following Ang II infusion in female HAF offspring.