Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Acta Physiol (Oxf). 2013 Apr;207(4):732-41. doi: 10.1111/apha.12079. Epub 2013 Feb 25.
Early life reduction in nephron number and chronic high salt intake cause development of renal and cardiovascular disease, which has been associated with oxidative stress and nitric oxide (NO) deficiency. We investigated the hypothesis that interventions stimulating NO signalling or reducing oxidative stress may restore renal autoregulation, attenuate hypertension and reduce renal and cardiovascular injuries following reduction in renal mass and chronic high salt intake.
Male Sprague-Dawley rats were uninephrectomized (UNX) or sham-operated at 3 weeks of age and given either a normal-salt (NS) or high-salt (HS) diet. Effects on renal and cardiovascular functions were assessed in rats supplemented with substrate for NO synthase (L-Arg) or a superoxide dismutase mimetic (Tempol).
Rats with UNX + HS developed hypertension and displayed increased renal NADPH oxidase activity, elevated levels of oxidative stress markers in plasma and urine, and reduced cGMP in plasma. Histological analysis showed signs of cardiac and renal inflammation and fibrosis. These changes were linked with abnormal renal autoregulation, measured as a stronger tubuloglomerular feedback (TGF) response. Simultaneous treatment with L-Arg or Tempol restored cGMP levels in plasma and increased markers of NO signalling in the kidney. This was associated with normalized TGF responses, attenuated hypertension and reduced signs of histopathological changes in the kidney and in the heart.
Reduction in nephron number during early life followed by chronic HS intake is associated with oxidative stress, impaired renal autoregulation and development of hypertension. Treatment strategies that increase NO bioavailability, or reduce levels of reactive oxygen species, were proven beneficial in this model of renal and cardiovascular disease.
在生命早期减少肾单位数量和长期高盐摄入会导致肾脏和心血管疾病的发生，这与氧化应激和一氧化氮（NO）缺乏有关。我们假设，刺激 NO 信号或减少氧化应激的干预措施可能会恢复肾脏自身调节功能，减轻高血压，并减少肾脏和心血管损伤，这些损伤是由肾脏减少和长期高盐摄入引起的。
雄性 Sprague-Dawley 大鼠在 3 周龄时进行单侧肾切除术（UNX）或假手术，并给予正常盐（NS）或高盐（HS）饮食。在补充 NO 合酶底物（L-Arg）或超氧化物歧化酶类似物（Tempol）的大鼠中，评估其对肾脏和心血管功能的影响。
UNX+HS 的大鼠发生高血压，并显示肾脏 NADPH 氧化酶活性增加，血浆和尿液中氧化应激标志物水平升高，血浆中环磷酸鸟苷（cGMP）减少。组织学分析显示心脏和肾脏炎症和纤维化的迹象。这些变化与异常的肾脏自身调节有关，表现为更强的管球反馈（TGF）反应。同时给予 L-Arg 或 Tempol 可恢复血浆中环磷酸鸟苷（cGMP）水平，并增加肾脏中 NO 信号标志物的水平。这与 TGF 反应的正常化、高血压的减轻以及肾脏和心脏组织病理学变化的减少有关。
生命早期减少肾单位数量，随后长期高盐摄入，与氧化应激、肾脏自身调节受损和高血压的发生有关。增加 NO 生物利用度或降低活性氧水平的治疗策略在这种肾脏和心血管疾病模型中被证明是有益的。
