Adoptive Transfer Reveals That T Cell-Derived Reactive Oxygen Species Contributes To Pregnancy-Induced Renal Damage In The Dahl SS Rat

Previous work from our lab demonstrated that Dahl SS rats develop a pregnancy-specific increase in blood pressure and proteinuria, also known as maternal syndrome (MS). Both T cells and reactive oxygen species (ROS) have been implicated in MS, and genetic deletion of either resulted in protection from MS in the Dahl SS rat. Therefore, we tested the hypothesis that ROS produced from T cells contributes to the development of MS in the Dahl SS. An adoptive transfer of splenocytes was utilized to reconstitute T cells from wild type Dahl SS (SS→CD247) or SS p67phox-/- (p67phox→CD247), which lack the ability to generate NOX2-derived ROS, into SS CD247-/- rats by intraperitoneal injection at postnatal day 5 to investigate the oxidative capacity of T cells. Injected SS CD247-/- rats were mated at 9-11 weeks of age with naïve littermate males, and virgin controls were run in parallel. Baseline protein excretion rates were comparable between mated groups (72±12 vs 66±9 mg/day, p> 0.05, n=10/group, SS→CD247 vs p67phox→CD247, respectively), yet the SS→CD247 develop an increase in proteinuria throughout pregnancy that is significantly elevated relative to p67phox→CD247 rats (217±65 vs 114±14 mg/day, p< 0.05). There was a trending decrease in creatinine clearance in the SS→CD247 vs p67phox→CD247 at the end of the study (0.37±0.03 vs 0.46±0.06, p =0.1), but MAP did not differ between groups. There was however, an increase in uterine artery resistance index as assessed by Doppler ultrasound at GD20 in the SS→CD247 relative p67phox→CD247 (0.72±0.03 vs 0.61±0.02, p <0.01) indicating an impairment in blood flow leading to the placenta. While, there was no difference observed in the number of infiltrating leukocytes into the kidneys between SS→CD247 vs p67phox→CD247, a significant correlation was observed between the number of infiltrating CD4+ T cells and the late pregnancy proteinuria levels (R 2 =0.7973) in the SS→CD247 mated group while no correlation was observed in the p67phox→CD247 (R 2 =0.0472). Taken together, adoptive transfer of T cells lacking NOX2 into SS CD247-/- rats fails to induce pregnancy associated renal damage and uterine artery blood flow impairment indicating a potential role for ROS in MS.