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

Szabina Czirok,Lilla Fang,Tamás Radovits,Gábor Kökény,Gábor Szénási,László Rosivall,Gábor Szabó,Béla Merkely

doi:10.1038/s41598-017-10125-3

Szabina Czirok, Lilla Fang + Show 6 more

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https://doi.org/10.1038/s41598-017-10125-3

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Journal: Scientific Reports	Publication Date: Sep 11, 2017
Citations: 21	License type: open-access

Affiliation: Semmelweis University, Heidelberg University

Abstract

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.

Highlights

The prevalence of chronic kidney disease is estimated to be 8–16% worldwide, and was ranked 18th in the list of causes of total number of global deaths in 20101
The altered production of endothelial nitric oxide (NO) – through hemodynamic and paracrine effects between endothelial cells, podocytes and mesangial cells – and decreased glomerular cyclic 3′,5′ guanosine monophosphate levels are suggested to account for the expansive pathology in DN9, 10
Soluble guanylate cyclase, which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate, and cGMP mediates the biological functions of NO15

Summary

Introduction

The prevalence of chronic kidney disease is estimated to be 8–16% worldwide, and was ranked 18th in the list of causes of total number of global deaths in 20101. The altered production of endothelial nitric oxide (NO) – through hemodynamic and paracrine effects between endothelial cells, podocytes and mesangial cells – and decreased glomerular cyclic 3′,5′ guanosine monophosphate (cGMP) levels are suggested to account for the expansive pathology in DN9, 10. Both in vivo and in vitro studies suggest, that the NO-cGMP axis plays an important role in the maintenance of renal perfusion and glomerular filtration[11], apart from its antifibrotic properties (due to reduced TGF-ß and extracellular matrix production[12,13,14] and inhibition of cell proliferation[10]). Among hemodynamic actions[11, 12], the NO–driven cGMP is important for normal podocyte function by maintaining the proper organization of slit diaphragm and cytoskeleton in podocytes[13, 14]

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