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), SSCD247-/- (Dahl SS CD247 knockout rat; lacking T cells), and SSp67phox-/- (Dahl SS p67phox [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, SSCD247-/-, and SSp67phox-/- 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 SSp67phox-/- donors into SSCD247-/- 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 SSp67phox-/- rat. To demonstrate that NOX2 in T cells contributes to adverse pregnancy phenotypes, adoptive transfer of SS splenocytes into SSCD247-/- rats resulted in significant pregnancy-induced renal damage, whereas transfer of SSp67phox-/- 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 SSp67phox-/- 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.

中文翻译：

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T 细胞中的完整 NOX2 介导 Dahl SS 大鼠妊娠诱导的肾损伤。


背景 妊娠期高血压疾病与心血管疾病、肾病和死亡风险增加有关。虽然确切的机制尚不清楚，但 T 细胞和活性氧与其发病机制有关。我们利用 Dahl 盐敏感 （SS）、SSCD247-/-（Dahl SS CD247 敲除大鼠;缺乏 T 细胞）和 SSp67phox-/-（Dahl SS p67phox [NOX2 （NADPH [NADPH [nitcotinamide 腺嘌呤二核苷酸磷酸]氧化酶 2）] 敲除大鼠研究初孕和多孕状态下的这些机制。方法 我们评估了 SS 、 SSCD247-/- 和 SSp67phox-/- 大鼠在初孕和多孕状态下的血压和肾损伤表型。为了研究 NOX2 在 T 细胞中的贡献，我们将脾细胞或分化簇 （CD）4+ T 细胞从 SS 或 SSp67phox-/- 供体过继转移到 SSCD247-/- 受体中，以确定妊娠表型的改变。结果 Multigravida SS 大鼠发生显著的妊娠诱导性肾损伤和肾功能损害，与孕产妇死亡率升高相关，而 T 细胞或 NOX2 缺失获得保护。在初产期，观察到肾损伤的这种减弱，在 SSp67phox-/- 大鼠中保护作用最大。为了证明 T 细胞中的 NOX2 与不良妊娠表型有关，SS 脾细胞过继转移到 SSCD247-/- 大鼠中导致显着的妊娠诱导性肾损伤，而 SSp67phox-/- 脾细胞的转移获得了保护。具体来说，SS CD4+ T 细胞的转移导致妊娠诱导的蛋白尿和子宫动脉阻力指数增加，这是 SSp67phox-/- CD4+ T 细胞转移未见的效果。 结论 T 细胞和 NOX2 衍生的活性氧因此，导致 SS 大鼠初产妊娠和多孕期妊娠的终末器官损伤，导致孕产妇死亡率增加。