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2017 ; 7
(1
): 11218
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Cinaciguat ameliorates glomerular damage by reducing ERK1/2 activity and TGF-ß
expression in type-1 diabetic rats
#MMPMID28894114
Czirok S
; Fang L
; Radovits T
; Szabó G
; Szénási G
; Rosivall L
; Merkely B
; Kökény G
Sci Rep
2017[Sep]; 7
(1
): 11218
PMID28894114
show ga
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.