Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Mitochondrial Biology Unit, Medical Research Council, University of Cambridge, Cambridge, United Kingdom.
Redox Biol. 2021 Jul;43:101961. doi: 10.1016/j.redox.2021.101961. Epub 2021 Apr 2.
Hydrogen sulfide (HS) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, HS is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. HS-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, HS is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of HS are not precisely understood. HS modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, HS affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by HS. HS enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of HS anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal HS levels. Together, HS is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of HS not only expands fundamental insight in the regulation of functional effects mediated by HS, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.
硫化氢（HS）长期以来一直被认为是一种恶臭、有毒的气体。然而，由于过去二十年中密集的生化研究，HS 现在被认为是哺乳动物系统中与一氧化氮（NO）和一氧化碳（CO）并列的第三气体递质。产生 HS 的酶在所有器官中表达，在其生理功能中发挥重要作用。在肾脏中，HS 是血管和细胞功能的关键调节剂，尽管影响 HS（亚）细胞水平的机制尚不完全清楚。HS 通过直接抑制一氧化氮合成来调节全身和肾血流量、肾小球滤过率和肾素-血管紧张素轴。此外，HS 通过通过翻译后蛋白修饰（即过硫化作用）来调节蛋白活性，从而影响细胞功能。过硫化作用调节蛋白活性、蛋白定位和蛋白-蛋白相互作用。此外，由于缺氧或缺血再灌注（IR）期间线粒体功能障碍导致的急性肾损伤（AKI）也可以被 HS 减轻。HS 增强 ATP 产生、防止自由基引起的损伤并在 IR 期间调节内质网应激。在这篇综述中，我们讨论了 HS 生物合成、保留和分解代谢的（亚）细胞调节的最新见解，这与肾脏 HS 水平的时空调节有关。总的来说，HS 是一种多功能的气体递质，对肾功能具有多种作用，并能提供对 AKI 的保护。阐明调节 HS（亚）细胞信号的机制不仅扩展了对 HS 介导的功能效应的调节的基本认识，而且还可以为预防缺氧或缺血性损伤引起的肾损伤提供新的治疗靶点。
