Harloff Manuela, Prüschenk Sally, Seifert Roland, Schlossmann Jens
Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany.
Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
Br J Pharmacol. 2022 Jun;179(11):2460-2475. doi: 10.1111/bph.15425. Epub 2021 May 4.
Diabetic nephropathy is the leading cause for end-stage renal disease worldwide. Until now, there is no specific therapy available. Standard treatment with inhibitors of the renin-angiotensin system just slows down progression. However, targeting the NO/sGC/cGMP pathway using sGC activators does prevent kidney damage. Thus, we investigated if the sGC activator cinaciguat was beneficial in a mouse model of diabetic nephropathy, and we analysed how mesangial cells (MCs) were affected by related conditions in cell culture.
Type 1 diabetes was induced with streptozotocin in wild-type and endothelial NOS knockout (eNOS KO) mice for 8 or 12 weeks.. Half of these mice received cinaciguat in their chow for the last 4 weeks. Kidneys from the diabetic mice were analysed with histochemical assays and by RT-PCR and western blotting. . Additionally, primary murine MCs under diabetic conditions were stimulated with 8-Br-cGMP or cinaciguat to activate the sGC/cGMP pathway.
The diabetic eNOS KO mice developed most characteristics of diabetic nephropathy, most marked at 12 weeks. Treatment with cinaciguat markedly improved GFR, serum creatinine, mesangial expansion and kidney fibrosis in these animals. We determined expression levels of related signalling proteins. Thrombospondin 1, a key mediator in kidney diseases, was strongly up-regulated under diabetic conditions and this increase was suppressed by activation of sGC/cGMP signalling.
Activation of the NO/sGC/PKG pathway with cinaciguat was beneficial in a model of diabetic nephropathy. Activators of sGC might be an appropriate therapy option in patients with Type 1 diabetes.
This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
糖尿病肾病是全球终末期肾病的主要病因。迄今为止，尚无特效疗法。使用肾素 - 血管紧张素系统抑制剂的标准治疗只能减缓疾病进展。然而，使用可溶性鸟苷酸环化酶（sGC）激活剂靶向一氧化氮（NO）/sGC/环磷酸鸟苷（cGMP）途径可预防肾脏损伤。因此，我们研究了sGC激活剂西那吉多在糖尿病肾病小鼠模型中是否有益，并分析了系膜细胞（MCs）在细胞培养中如何受到相关条件的影响。
用链脲佐菌素诱导野生型和内皮型一氧化氮合酶基因敲除（eNOS KO）小鼠患1型糖尿病8周或12周。在最后4周，这些小鼠中有一半在食物中添加西那吉多。对糖尿病小鼠的肾脏进行组织化学分析、逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹分析。此外，在糖尿病条件下，用8-溴-cGMP或西那吉多刺激原代小鼠系膜细胞，以激活sGC/cGMP途径。
糖尿病eNOS KO小鼠出现了糖尿病肾病的大多数特征，在12周时最为明显。用西那吉多治疗可显著改善这些动物的肾小球滤过率（GFR）、血清肌酐、系膜扩张和肾纤维化。我们测定了相关信号蛋白的表达水平。血小板反应蛋白1是肾脏疾病中的关键介质，在糖尿病条件下强烈上调，而这种增加通过激活sGC/cGMP信号传导受到抑制。
用西那吉多激活NO/sGC/蛋白激酶G（PKG）途径在糖尿病肾病模型中是有益的。sGC激活剂可能是1型糖尿病患者的一种合适治疗选择。
本文是关于细胞生长与存活中cGMP信号传导的主题系列文章的一部分。要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc。
