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

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.

Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

“…Although it is unclear how modulators of cGMP levels regulate CTGF expression in the lung, riociguat has been shown to decrease CTGF expression in progressive cardiac remodeling and failure after myocardial infarction [ 52 ]. Similarly, cinaciguat, a sGC activator, has also been shown to decrease CTGF expression and protect against glomerular damage in diabetic rats [ 53 ].…”

The PPARγ agonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3

“…Formaline fixed paraffin embedded kidney sections were evaluated after Masson’s trichrome staining. The degree of glomerulosclerosis and tubulointerstitial damage was determined blinded on a semiquantitative scale as previously described [23].…”

“…Immunohistochemical staining of paraffin embedded sections was performed using avidin-biotin method as previously described [23] using citrate buffer pH 6.0 for heat induced antigen retrieval. The primary antibodies were rabbit polyclonal anti-fibronectin at 1:1000 (Sigma-Aldrich, Budapest), and rabbit polyclonal anti-EGR-1 at 1:500 (Cell Signaling, USA).…”

The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective

“…In preclinical rat models, increased glomerular permeability by l -NAME was reduced by NO donors or cGMP agonist (8-bromo-cGMP) [ 39 ], suggesting a direct and pivotal role of NO/sGC/cGMP in the maintenance of glomerular permeability. sGC activation by cinaciguat (BAY 58-2667) restored glomerular cGMP content, sGC expression, reduced diabetes-induced proteinuria, glomerulosclerosis and fibrosis of diabetic rats [ 40 ]. Improvement of diabetes-induced glomerular damage by sGC activation was achieved by suppression of TGF- and ERK-1 signaling.…”