Dugbartey George J
Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Pharmacol Rep. 2017 Apr;69(2):331-339. doi: 10.1016/j.pharep.2016.11.004. Epub 2016 Nov 11.
Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease. Despite optimal management, DN is still a major contributor to morbidity and mortality of diabetic patients worldwide. The major pathological alterations in DN include excessive accumulation and deposition of extracellular matrix, leading to expansion of mesangial matrix, thickening of glomerular basement membrane and tubulointerstitial fibrosis. At the molecular level, accumulating evidence suggests that hyperglycemia or high glucose mediates renal injury in DN via multiple molecular mechanisms such as induction of oxidative stress, upregulation of renal transforming growth factor beta-1 expression, production of proinflammatory cytokines, activation of fibroblasts and renin angiotensin system, and depletion of adenosine triphosphate. Also worrying is the fact that existing therapies only retard the disease progression but do not prevent it. Therefore, there is urgent need to identify novel therapies to target additional disease mechanisms. Hydrogen sulfide (HS), the third member of the gasotransmitter family, has recently been identified and demonstrated to possess important therapeutic characteristics that prevent the development and progression of DN in experimental animals by targeting several important molecular pathways, and therefore may represent an alternative or additional therapeutic approach for DN. This review discusses recent experimental findings on the molecular mechanisms underlying the therapeutic effects of HS against the development and progression of DN and its clinical application in the future.
糖尿病肾病(DN)目前是终末期肾病的主要病因。尽管进行了最佳管理,但DN仍是全球糖尿病患者发病和死亡的主要原因。DN的主要病理改变包括细胞外基质的过度积聚和沉积,导致系膜基质扩张、肾小球基底膜增厚和肾小管间质纤维化。在分子水平上,越来越多的证据表明,高血糖或高糖通过多种分子机制介导DN中的肾损伤,如诱导氧化应激、上调肾转化生长因子β-1表达、产生促炎细胞因子、激活成纤维细胞和肾素血管紧张素系统以及三磷酸腺苷耗竭。同样令人担忧的是,现有疗法仅能延缓疾病进展,却无法预防。因此,迫切需要确定针对其他疾病机制的新疗法。硫化氢(HS)作为气体信号分子家族的第三个成员,最近已被确定并证明具有重要的治疗特性,通过靶向几个重要的分子途径来预防实验动物中DN的发生和发展,因此可能代表DN的一种替代或补充治疗方法。本综述讨论了关于HS对DN发生和发展的治疗作用的分子机制的最新实验发现及其未来的临床应用。