Harloff, Manuela and Prüschenk, Sally and Seifert, Roland and Schlossmann, Jens (2022) Activation of soluble guanylyl cyclase signalling with cinaciguat improves impaired kidney function in diabetic mice. BRITISH JOURNAL OF PHARMACOLOGY, 179 (11). pp. 2460-2475. ISSN 0007-1188, 1476-5381
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ATRIAL-NATRIURETIC-PEPTIDE; PROTEIN-KINASE I; NITRIC-OXIDE; OXIDATIVE STRESS; MESANGIAL CELL; CONCISE GUIDE; LONG-TERM; NEPHROPATHY; INHIBITION; DISEASE; cGMP; cinaciguat; diabetic nephropathy; mesangial cells; PKG; sGC activator |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Petra Gürster |
| Date Deposited: | 07 Nov 2024 10:45 |
| Last Modified: | 07 Nov 2024 10:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46438 |
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