Study of Acute Kidney Injury in hyperandrogenemic female rats

Abstract

Chronic hyperandrogenemia is hallmark of polycystic ovarian syndrome (PCOS), affecting ~10% of women of reproductive age. Compared to men, women are protected against ischemia‐ reperfusion (I/R) acute kidney injury (AKI), but the potential susceptibility of women that have elevated androgens, as women with PCOS, to develop I/R‐induced AKI is not clear. Other models of hyperandrogenemia in females in which I/R AKI was studied utilized levels of testosterone similar to males. Using an established female rat model of PCOS that has a 3 fold increase in DHT, such as women with PCOS and 10 fold lower than in males, we tested the hypothesis that chronic hyperandrogenemia increases the risk of I/R‐induced AKI compare to placebo controls. Female SD rats were implanted with dihydrotestosterone (DHT, 7.5mg/90d) or placebo pellets (n=11/grp) beginning at 6 wks of age; pellets were changed every 85 d. At 6–7 mos of age, rats (n=3–4/grp) were subjected to sham or renal I/R with bilateral clamping of renal vessels for 30 min at 37±0.5°C. Rats were placed in metabolism cages for 24hrs reperfusion. At 48–72hr post‐surgery rats were again put in metabolic cages for 24hr, and then euthanized for blood and tissue samples. I/R increased plasma creatinine (PCr) 24hr post reperfusion in placebo (2.58±0.34 vs 0.86±0.1 mg/dL, p<0.05) as well as DHT treated rats (4.53± 0.46 vs 0.9±0.06 mg/dL, P<0.001) compared to sham‐I/R group. As noted, PCr in DHT‐treated rats was significantly higher than in placebo rats (4.53± 0.46 vs 2.58±0.34 mg/dL, p<0.05). When DHT rats were pre‐treated with androgen receptor antagonist (Flutamide, 30mg/kg/day, s.c.) for three days prior to I/R, PCr levels 24hr post reperfusion were not different than DHT–treated I/R groups (4.75 0.52 vs 4.53± 0.46 mg/dL, p=ns). These data show that rat exposure to chronic hyperandrogenemia causes significantly greater renal injury in response to I/R AKI than in controls. This injury is independent of the androgen receptor suggesting other mechanisms may be contributing to the higher level of renal injury after I/R AKI in females with PCOS.Support or Funding InformationSupported by NIH R01HL66072, P01HL05971.