Abstract T4: Nox2-derived Reactive Oxygen Species Contribute To The Impaired Renal Function And Increased Maternal Mortality Observed In Dahl SS Rats Following Multiple Pregnancies

Abstract

We recently demonstrated that female Dahl Salt-Sensitive (SS) rats develop significant proteinuria, reduced renal function, and increased mortality (greater than 50% compared to virgin controls) following multiple pregnancies while fed a low salt diet. While the mechanisms are unclear, it is proposed that reactive oxygen species (ROS) production contributes to this renal disease phenotype. Previous experiments demonstrated that NADPH oxidase (NOX) 2-derived ROS production mediates the development of maternal syndrome (hypertension and proteinuria) in Dahl SS rat during a singular pregnancy, yet the role of NOX 2-derived ROS on long term renal health and survival following multiple pregnancies has not been explored. Therefore, we tested the hypothesis that genetic deletion of the p67phox subunit of NOX2 (SS p67phox-/- ) will result in the protection from reduced renal function and maternal death following multiple pregnancies. There were no maternal deaths observed in the SS p67phox-/- virgin or mated rats (n=3-5/group) following three pregnancies, suggesting that the production of NOX2-derived ROS contributes to the increased mortality seen in the SS rats. In terms of renal damage, protein excretion levels were comparable at baseline between virgin and mated SS p67phox-/- rats (26.3±2.8 vs 19.6±3.8 mg/day, p >0.05). Unlike the SS rats that develop significant proteinuria at the end of three pregnancies (217±53 mg/day, n=7), the SS p67phox-/- rats do not develop a pregnancy-specific increase in proteinuria as they remain comparable to the virgin controls following three pregnancies (31.8±10 vs 50.7±14 mg/day, p >0.05). Furthermore, the mated SS p67phox-/- do not exhibit changes in creatinine clearance (0.65±0.1 vs 0.62±0.1 ml/min/g, p >0.05) or blood urea nitrogen (BUN) levels (16±2 vs 15.7±1.3 mg/dl, p >0.05) relative to virgin controls. In contrast, SS rats develop significant impairment in renal function (creatinine clearance: 0.39±0.06 ml/min/g and BUN: 26.9±2.9) following multiple pregnancies, suggesting that NOX2-derived ROS contribute to the significant renal damage phenotype observed in the SS rats. Further studies are necessary to identify the cell type responsible for producing the detrimental ROS contributing to this phenotype.