Cinaciguat ameliorates glomerular damage by reducing ERK1/2 activity and TGF-ß expression in type-1 diabetic rats

Autor:	Tamás Radovits, Gábor Szabó, Lilla Fang, Szabina Czirok, Béla Merkely, László Rosivall, Gabor Kokeny, Gábor Szénási
Jazyk:	angličtina
Rok vydání:	2017
Předmět:	0301 basic medicine Male medicine.medical_specialty MAP Kinase Signaling System 030232 urology & nephrology Enzyme Activators lcsh:Medicine Kidney Benzoates Article Nephropathy Podocyte Diabetes Mellitus Experimental Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cinaciguat Transforming Growth Factor beta Diabetes mellitus Internal medicine medicine Animals Diabetic Nephropathies lcsh:Science Cyclic GMP Multidisciplinary TUNEL assay business.industry Guanylate cyclase activity lcsh:R Glomerulosclerosis medicine.disease Streptozotocin Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Diabetes Mellitus Type 1 Treatment Outcome chemistry lcsh:Q business medicine.drug
Zdroj:	Scientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
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