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.

Epigenetic regulation of cardiac fibrosis

“…In a model of diabetic renal fibrosis induced by streptozotocin (STZ), C66, a curcumin analog, blocked glomerular and interstitial fibrosis, which was associated with reduced renal mitogen activated protein kinase (MAPK) signaling [53, 54]. Chromatin immunoprecipitation (ChIP) revealed that C66 reduced STZ-mediated recruitment of p300 to the promoters for the genes encoding CTGF, PAI-1 and fibronectin, and this was associated with reduced H3K9/14 acetylation at these sites.…”

Inhibition of JNK by compound C66 prevents pathological changes of the aorta in STZ‐induced diabetes

“…We have synthesized a few of novel curcumin analogues . Among these analogues, C66 was found to effectively inhibit high glucose (HG)‐induced inflammatory response and macrophage infiltration, resulting in a significant prevention of renal injury in diabetic rats . However, whether C66 is able to prevent diabetes‐induced vascular damage via up‐regulation of Nrf2 and its downstream antioxidant proteins has not been addressed yet.…”

Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

“…Inflammation initiates the progress of renal abnormal homeostasis leading to acute and chronic renal damages. 20,21 Macrophage infiltration was significantly correlated with the extent of glomerulosclerosis, interstitial fibrosis and glomerular hypertrophy in human renal injuries. 28 Previous findings have supported that proinflammatory cytokines, such as TNF-α, IL-6 and iNOS, obviously increased in obese mouse proximal tubule and glomerular cells.…”

“…Compared with lean mice, the mRNA of Klf4 was time dependently decreased in HFD-fed mice ( Figure 1A). [19][20][21][22] As showed in Figure 1D Circulating creatinine and blood urea nitrogen (BUN) are crucial parameters for defining renal dysfunction.…”

“…NF-κB signalling, as a crucial transcriptional factor in regulating inflammatory response, is widely studied in metabolic diseases 20,21. To disclose the effects of KLF4 on renal function, we firstly overexpressed Klf4 levels to identify the consequences in vitro.…”