Open AccessInhibition of MAPK ‐mediated ACE expression by compound C66 prevents STZ ‐induced diabetic nephropathy
Author(s) -
Pan Yong,
Huang Yi,
Wang Zhe,
Fang Qilu,
Sun Yusheng,
Tong Chao,
Peng Kesong,
Wang Yangwei,
Miao Lining,
Cai Lu,
Zhao Yunjie,
Liang Guang
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12175
Subject(s) - mapk/erk pathway , diabetic nephropathy , angiotensin ii , renin–angiotensin system , protein kinase a , kinase , pharmacology , mitogen activated protein kinase , endocrinology , p38 mitogen activated protein kinases , medicine , chemistry , kidney , biology , microbiology and biotechnology , receptor , blood pressure
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, MAPK s 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 MAPK s inhibition seems to be an alternative strategy for the treatment of DN .