Activation of sGC signalling with Cinaciguat improves impaired kidney function in diabetic mice.
2021
BACKGROUND AND PURPOSE Diabetic nephropathy (DN) is the leading cause for end-stage renal disease worldwide. Until now, there is no specific therapy available. Standard treatment with inhibitors of renin-angiotensin system just slows down progression. However, targeting the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP pathway using sGC activators was shown to effectively prevent kidney damage. Thus, we investigated if the sGC activator cinaciguat shows beneficial effects in a mouse model of DN and we analysed how mesangial cells (MCs) were affected by related conditions in cell culture. EXPERIMENTAL APPROACH Kidneys from streptozotocin-induced type 1 diabetes wild-type and endothelial NOS knockout (eNOS KO) mice were analysed after 8 or 12 weeks observation time. Half of these mice received cinaciguat incorporated into their chow in the last four weeks. Additionally, primary murine MCs under diabetic conditions were stimulated with 8-Br-cGMP or cinaciguat to activate the sGC/cGMP pathway. KEY RESULTS Particularly 12 weeks DM eNOS KO mice developed most characteristics of DN. Treatment with cinaciguat markedly improved glomerular filtration rate, serum creatinine, mesangial expansion and kidney fibrosis in these animals. We further determined expression levels of related signalling proteins, and showed for example that Thrombospondin 1, a key mediator in kidney diseases, was strongly upregulated under diabetic conditions. This rise was suppressed by activation of sGC/cGMP signalling. CONCLUSION AND IMPLICATIONS These results demonstrate, that activation of the NO/sGC/PKG pathway with cinaciguat has beneficial effects on DN, indicating that sGC activators might be an appropriate therapy option.
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