Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
Sci Rep. 2017 Sep 11;7(1):11218. doi: 10.1038/s41598-017-10125-3.
Decreased soluble guanylate cyclase activity and cGMP levels in diabetic kidneys were shown to influence the progression of nephropathy. The regulatory effects of soluble guanylate cyclase activators on renal signaling pathways are still unknown, we therefore investigated the renal molecular effects of the soluble guanylate cyclase activator cinaciguat in type-1 diabetic (T1DM) rats. Male adult Sprague-Dawley rats were divided into 2 groups after induction of T1DM with 60 mg/kg streptozotocin: DM, untreated (DM, n = 8) and 2) DM + cinaciguat (10 mg/kg per os daily, DM-Cin, n = 8). Non-diabetic untreated and cinaciguat treated rats served as controls (Co (n = 10) and Co-Cin (n = 10), respectively). Rats were treated for eight weeks, when renal functional and molecular analyses were performed. Cinaciguat attenuated the diabetes induced proteinuria, glomerulosclerosis and renal collagen-IV expression accompanied by 50% reduction of TIMP-1 expression. Cinaciguat treatment restored the glomerular cGMP content and soluble guanylate cyclase expression, and ameliorated the glomerular apoptosis (TUNEL positive cell number) and podocyte injury. These effects were accompanied by significantly reduced TGF-ß overexpression and ERK1/2 phosphorylation in cinaciguat treated diabetic kidneys. We conclude that the soluble guanylate cyclase activator cinaciguat ameliorated diabetes induced glomerular damage, apoptosis, podocyte injury and TIMP-1 overexpression by suppressing TGF-ß and ERK1/2 signaling.
研究表明，糖尿病肾脏中可溶性鸟苷酸环化酶活性和 cGMP 水平的降低会影响肾病的进展。可溶性鸟苷酸环化酶激活剂对肾脏信号通路的调节作用尚不清楚，因此我们研究了可溶性鸟苷酸环化酶激活剂西那卡塞在 1 型糖尿病（T1DM）大鼠中的肾脏分子效应。雄性成年 Sprague-Dawley 大鼠经 60mg/kg 链脲佐菌素诱导 T1DM 后分为 2 组：DM，未治疗（DM，n=8）和 2）DM+西那卡塞（10mg/kg 口服，每日 1 次，DM-Cin，n=8）。未患糖尿病的未治疗和西那卡塞治疗大鼠分别作为对照（Co（n=10）和 Co-Cin（n=10））。大鼠治疗 8 周后，进行肾功能和分子分析。西那卡塞减轻了糖尿病诱导的蛋白尿、肾小球硬化和肾脏胶原-IV 表达，同时 TIMP-1 表达减少 50%。西那卡塞治疗恢复了肾小球 cGMP 含量和可溶性鸟苷酸环化酶表达，并改善了肾小球细胞凋亡（TUNEL 阳性细胞数）和足细胞损伤。这些作用伴随着 TGF-β过表达和 ERK1/2 磷酸化在西那卡塞治疗的糖尿病肾脏中显著降低。我们得出结论，可溶性鸟苷酸环化酶激活剂西那卡塞通过抑制 TGF-β和 ERK1/2 信号通路，改善了糖尿病诱导的肾小球损伤、细胞凋亡、足细胞损伤和 TIMP-1 过表达。
