Intact NOX2 in T Cells Mediates Pregnancy-Induced Renal Damage in Dahl SS Rats

Abstract

BACKGROUND: Hypertensive disorders of pregnancy are associated with increased risk for cardiovascular disease, renal disease, and mortality. While the exact mechanisms remain unclear, T cells and reactive oxygen species have been implicated in its pathogenesis. We utilized Dahl salt-sensitive (SS), SS CD247 −/− (Dahl SS CD247 knockout rat; lacking T cells), and SS p67phox−/− (Dahl SS p67 phox [NOX2 (NADPH oxidase 2)] knockout rat; lacking NOX2) rats to investigate these mechanisms in primigravida and multigravida states. METHODS: We assessed blood pressure and renal damage phenotypes in SS, SS CD247−/− , and SS p67phox−/− rats during primigravida and multigravida states. To investigate the contribution of NOX2 in T cells, we performed adoptive transfers of splenocytes or CD4 + T cells from either SS or SS p67phox−/− donors into SS CD247−/− recipients to determine pregnancy-specific alterations in phenotype. RESULTS: Multigravida SS rats developed significant pregnancy-induced renal damage and renal functional impairment associated with elevated maternal mortality rates, whereas deletion of T cells or NOX2 garnered protection. During primigravida states, this attenuation in renal damage was observed, with the greatest protection in the SS p67phox−/− rat. To demonstrate that NOX2 in T cells contributes to adverse pregnancy phenotypes, adoptive transfer of SS splenocytes into SS CD247−/− rats resulted in significant pregnancy-induced renal damage, whereas transfer of SS p67phox−/− splenocytes garnered protection. Specifically, the transfer of SS CD4 + T cells resulted in pregnancy-induced proteinuria and increases in uterine artery resistance index, an effect not seen with the transfer of SS p67phox−/− CD4 + T cells. CONCLUSIONS: T cells and NOX2-derived reactive oxygen species, thus, contribute to end-organ damage in both primigravida and multigravida pregnancies in the SS rat leading to increases in maternal mortality.