Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel curcumin derivative prevents renal injury in diabetic rats

Yong Pan, Yi Wang, Lu Cai, Yuepiao Cai, Jie Hu, Congcong Yu, Jianling Li, Zhiguo Feng, Shulin Yang, Xiaokun Li, Guang Liang
British Journal of Pharmacology 2012, 166 (3): 1169-82

BACKGROUND AND PURPOSE: Inflammation is involved in the development and/or progression of many diseases including diabetic complications. Investigations on novel anti-inflammatory agents may offer new approaches for the prevention of diabetic nephropathy. Our previous bioscreening of synthetic analogues of curcumin revealed C66 as a novel anti-inflammatory compound against LPS challenge in macrophages. In this study, we hypothesized that C66 affects high glucose (HG)-induced inflammation profiles in vitro and in vivo and then prevents renal injury in diabetic rats via its anti-inflammatory actions.

EXPERIMENTAL APPROACH: Primary peritoneal macrophages (MPM), prepared from C57BL/6 mice, were treated with HG in the presence or absence of C66. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and the effects of C66 (0.2, 1.0 or 5.0 mg·kg(-1) ), administered daily for 6 weeks, on plasma TNF-α levels and expression of inflammatory genes in the kidney were assessed.

KEY RESULTS: Pretreatment of MPMs with C66 reduced HG-stimulated production of TNF-α and NO, inhibited HG-induced IL-1β, TNF-α, IL-6, IL-12, COX-2 and iNOS mRNA transcription, and the activation of JNK/NF-kB signalling. In vivo, C66 inhibited the increased plasma TNF-α levels and renal inflammatory gene expression, improved histological abnormalities and fibrosis of diabetic kidney, but did not affect the hyperglycaemia in these diabetic rats.

CONCLUSIONS AND IMPLICATIONS: The anti-inflammatory effects of C66 are mediated by inhibiting HG-induced activation of the JNK/NF-κB pathway, rather than by reducing blood glucose in diabetic rats. This novel compound is a potential anti-inflammatory agent and might be beneficial for the prevention of diabetic nephropathy.

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