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

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 [nitcotinamide adenine dinucleotide phosphate] 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 cluster of differentiation (CD)4⁺ 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.