Manuela Harloff1, Sally Prüschenk1, Roland Seifert2,3, Jens Schlossmann1. 1. Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany. 2. Institute of Pharmacology, Hannover Medical School, Hannover, Germany. 3. Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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. LINKED ARTICLES: 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.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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. LINKED ARTICLES: 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.