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

被引:26
作者
Czirok, Szabina [1 ]
Fang, Lilla [1 ]
Radovits, Tamas [2 ]
Szabo, Gabor [3 ]
Szenasi, Gabor [1 ]
Rosivall, Laszlo [1 ]
Merkely, Bela [2 ]
Kokeny, Gabor [1 ]
机构
[1] Semmelweis Univ, Inst Pathophysiol, Budapest, Hungary
[2] Semmelweis Univ, Heart & Vasc Ctr, Budapest, Hungary
[3] Heidelberg Univ, Dept Cardiac Surg, Heidelberg, Germany
基金
匈牙利科学研究基金会;
关键词
SOLUBLE GUANYLATE-CYCLASE; NITRIC-OXIDE; GROWTH-FACTOR; HIGH GLUCOSE; OXIDATIVE STRESS; PODOCYTE INJURY; GENE-EXPRESSION; MESANGIAL CELLS; KIDNEY-DISEASE; MAP KINASE;
D O I
10.1038/s41598-017-10125-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 SpragueDawley 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-beta 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-beta and ERK1/2 signaling.
引用
收藏
页数:15
相关论文
共 61 条
[1]   Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes [J].
Alfano, Massimo ;
Cinque, Paola ;
Giusti, Guido ;
Proietti, Silvia ;
Nebuloni, Manuela ;
Danese, Silvio ;
D'Alessio, Silvia ;
Genua, Marco ;
Portale, Federica ;
Lo Porto, Manuela ;
Singhal, Pravin C. ;
Rastaldi, Maria Pia ;
Saleem, Moin A. ;
Mavilio, Domenico ;
Mikulak, Joanna .
SCIENTIFIC REPORTS, 2015, 5
[2]  
BALLERMANN BJ, 1991, CLIN INVEST MED, V14, P508
[3]   Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling [J].
Beyer, Christian ;
Zenzmaier, Christoph ;
Palumbo-Zerr, Katrin ;
Mancuso, Rossella ;
Distler, Alfiya ;
Dees, Clara ;
Zerr, Pawel ;
Huang, Jingang ;
Maier, Christiane ;
Pachowsky, Milena L. ;
Friebe, Andreas ;
Sandner, Peter ;
Distler, Oliver ;
Schett, Georg ;
Berger, Peter ;
Distler, Joerg H. W. .
ANNALS OF THE RHEUMATIC DISEASES, 2015, 74 (07) :1408-1416
[4]   Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury [J].
Blattner, Simone M. ;
Hodgin, Jeffrey B. ;
Nishio, Masashi ;
Wylie, Stephanie A. ;
Saha, Jharna ;
Soofi, Abdul A. ;
Vining, Courtenay ;
Randolph, Ann ;
Herbach, Nadja ;
Wanke, Ruediger ;
Atkins, Kevin B. ;
Kang, Hee Gyung ;
Henger, Anna ;
Brakebusch, Cord ;
Holzman, Lawrence B. ;
Kretzler, Matthias .
KIDNEY INTERNATIONAL, 2013, 84 (05) :920-930
[5]   A Soluble Guanylate Cyclase Activator Inhibits the Progression of Diabetic Nephropathy in the ZSF1 Rat [J].
Boustany-Kari, Carine M. ;
Harrison, Paul C. ;
Chen, Hongxing ;
Lincoln, Kathleen A. ;
Qian, Hu Sheng ;
Clifford, Holly ;
Wang, Hong ;
Zhang, Xiaomei ;
Gueneva-Boucheva, Kristina ;
Bosanac, Todd ;
Wong, Diane ;
Fryer, Ryan M. ;
Richman, Jeremy G. ;
Sarko, Chris ;
Pullen, Steven S. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2016, 356 (03) :712-719
[6]   The renin-angiotensin-aidosterone system: Cardiorenal effects and implications for renal and cardiovascular disease states [J].
Brewster, UC ;
Setaro, JF ;
Perazella, MA .
AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 2003, 326 (01) :15-24
[7]   IMPAIRED NITRIC OXIDE-DEPENDENT CYCLIC GUANOSINE-MONOPHOSPHATE GENERATION IN GLOMERULI FROM DIABETIC RATS - EVIDENCE FOR PROTEIN-KINASE C-MEDIATED SUPPRESSION OF THE CHOLINERGIC RESPONSE [J].
CRAVEN, PA ;
STUDER, RK ;
DERUBERTIS, FR .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (01) :311-320
[8]   Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis [J].
Cui, Wenpeng ;
Maimaitiyiming, Hasiyeti ;
Qi, Xinyu ;
Norman, Heather ;
Zhou, Qi ;
Wang, Xiaojun ;
Fu, Jian ;
Wang, Shuxia .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2014, 306 (09) :F996-F1007
[9]   Mechanical forces and TGFβ1 reduce podocyte adhesion through α3β1 integrin downregulation [J].
Dessapt, Cecile ;
Baradez, Marc Olivier ;
Hayward, Anthea ;
Dei Cas, Alessandra ;
Thomas, Stephen M. ;
Viberti, Giancarlo ;
Gnudi, Luigi .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2009, 24 (09) :2645-2655
[10]   Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation [J].
Dlugosz, JA ;
Munk, S ;
Kapor-Drezgic, J ;
Goldberg, HJ ;
Fantus, IG ;
Scholey, JW ;
Whiteside, CI .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2000, 279 (04) :F688-F697