Protection Effects Of Novel Curcumin Analog C66on Type1Diabetes-induced Renal Complications Via JNK Pathway With The Involvement Of P300/CBP-mediated Histone Acetylation

Diabetic nephropathy (DN), one of the major diabetic complications and themost common cause of end-stage kidney disease. The exact cause of DN is unknown,but several pathogenic factors such as genetic, environmental and hemodynamicfactors may cause oxidative stress and inflammation, leading to the accumulation ofextracellular matrix (ECM) proteins and renal glomerulosclerosis (fibrosis), followedfinally by glomerular dysfunction and renal failure. The pro-inflammatory cytokinessuch as MCP-1,ICAM-1and VCAM-1,the fibrotic cytokines such asTGF-β,CTGF,PAI1and FN1, all play important roles in the development andprogression of diabetic renal complication. Curcumin, a polyphenol,derived from theturmeric, has been extensively demonstrated a lot of pharmacological effects, such asanti-inflammatory, anti-oxidative, anticancer, anti-fibrosis activities. C66, a curcuminanalogue, was proved to significantly inhibit the HG-induced inflammatory responsein mouse kidney.The present study aimed to investigate whether curcumin analog C66can preventDN in streptozotocin-induced diabetic mice via inhibition of JNK pathway andepigenetic histone acetylation. The type1diabetes mouse model was induced withstreptozotocin （STZ）using C57BL/6J mice strain. Both control and diabetic micewere randomly divided into three groups, were treated separately by gavage with1%CMC-Na solution, C66and JNKi (C66and JNKi dissolved in1%CMC-Na solution).All solutions were administered at5mg/kg, every other day for3months. At the endof3-month treatment, one set of both diabetic and control mice were sacrificed,labeled as3month (3M) study. Another set of both diabetic and control mice wereaged for additional3months without further treatment as6month (6M) study.Firstly, we investigated the protection effects of C66on diabetes mice kidneysvia examination of renal functional changes and renal histological structural changes,the expressions of renal pro-inflammatory cytokines and fibroticcytokines.The results showed that C66alleviated the renal dysfunction and renalstructural changes in diabetic mice. Interestingly, in6M mice, even aged foradditional3months without further administration, we found diabetic mice treatedwith C66exhibited sustained renal protection effects. Meanwhile, we found in ourstudy, C66significantly prevented the upregulation of the expressions ofpro-inflammatory cytokines MCP-1,ICAM-1and VCAM-1and fibrotic cytokinesTGF-β,CTGF,PAI1and FN1induced by diabetes.Then we measured the influence of C66on the renal JNK pathway and histoneacetylation in diabetic mice, followed by the H3K9/14Ac level and p300/CBPoccupancy on the promoters of CTGF, PAI-1, and FN-1gene, in order to investigatethe mechanisms of renal protection of C66in diabetic mice. In our study, wedemonstrated for the first time that C66prevented diabetic nephropathy via JNKpathway with the involvement of p300/CBP-mediated histone acetylation, thereby therenal protection effects. And this effects sustained longtime even the C66treatmentsuspended because of the prevention of C66on “metabolic memory” associatedwith persistent epigenetic modifications and p300/CBP activation via loopautoacetylaed.In summary, our study provides extensive evidence that C66has sustained renalprotection effects in diabetes through effectively preventing the JNK pathwayactivation followed by the overexpression of histone acetylation.And the JNKpathway and p300/CBP-mediated Histone Acetylation may be one of the new therapystrategies of diabetic complications.