title: Inhibition of MAPK-mediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy.
abstract: A range of in vitro, experimental and clinical intervention studies have implicated an important role for hyperglycaemia-induced activation of the renin-angiotensin system (RAS) in the development and progression of diabetic nephropathy (DN). Blockade of RAS by angiotensin converting enzyme (ACE) inhibitors is an effective strategy in treating diabetic kidney diseases. However, few studies demonstrate the mechanism by which hyperglycaemia up-regulates the expression of ACE gene. Our previous studies have identified a novel curcumin analogue, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66), which could inhibit the high glucose (HG)-induced phosphorylation of mitogen-activated protein kinases in mouse macrophages. In this study, we found that the renal protection of C66 in diabetic mice was associated with mitogen-activated protein kinase (MAPK) inactivation and ACE/angiotensin II (Ang II) down-regulation. Generally, MAPKs have been considered as a downstream signalling of Ang II and a mediator for Ang II-induced pathophysiological actions. However, using C66 and specific inhibitors as small molecule probes, in vitro experiments demonstrate that the MAPK signalling pathway regulates ACE expression under HG stimulation, which contributes to renal Ang II activation and the development of DN. This study indicates that C66 is a potential candidate of DN therapeutic agents, and more importantly, that reduction in ACE expression by MAPKs inhibition seems to be an alternative strategy for the treatment of DN.
authors: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors: Yong
authors: Y
authors: Pan
authors: Yi
authors: Y
authors: Huang
authors: Zhe
authors: Z
authors: Wang
authors: Qilu
authors: Q
authors: Fang
authors: Yusheng
authors: Y
authors: Sun
authors: Chao
authors: C
authors: Tong
authors: Kesong
authors: K
authors: Peng
authors: Yangwei
authors: Y
authors: Wang
authors: Lining
authors: L
authors: Miao
authors: Lu
authors: L
authors: Cai
authors: Yunjie
authors: Y
authors: Zhao
authors: Guang
authors: G
authors: Liang
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D003512:Cyclohexanones / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: C575443:2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone; D001597:Benzylidene Compounds; D003512:Cyclohexanones; D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; D013311:Streptozocin; D020928:Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A
keywords: (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone; angiotensin converting enzyme; diabetic nephropathy; mitogen-activated protein kinases; renin-angiotensin system