Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Nat Rev Nephrol. 2021 Sep;17(9):575-590. doi: 10.1038/s41581-021-00429-z. Epub 2021 Jun 1.
The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic L-arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate-nitrite-NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.
心血管和代谢性疾病加上肾功能障碍的流行在全球范围内不断增加。这种三联症与相当大的发病率和死亡率以及巨大的经济负担有关。进一步了解潜在的病理生理机制对于开发新的预防或治疗方法很重要。在提出的机制中，与氧化应激相关的受损的一氧化氮（NO）生物活性被认为是重要的。NO 是一种短寿命的双原子信号分子，对肾脏、心脏和血管以及周围代谢活跃的器官发挥多种作用。酶促 L-精氨酸依赖性一氧化氮合酶（NOS）途径被经典地视为内源性 NO 形成的主要来源。然而，NOS 系统的功能在包括肾脏、心血管和代谢疾病在内的各种病理中经常受到损害。替代途径，硝酸盐-亚硝酸盐-NO 途径，使内源性或膳食衍生的无机硝酸盐和亚硝酸盐能够通过连续还原循环回收，形成包括 NO 在内的生物活性氮物种，而不依赖于 NOS 系统。这些氮物种的信号转导与 cGMP 依赖性和非依赖性机制有关。在 NOS 缺乏和氧化应激期间恢复 NO 动态平衡的新方法在肾脏、心血管和代谢疾病中具有潜在的治疗应用。
