HDAC6调控内源性IL-10表达缓解糖尿病肾病炎症反应

Inflammation is a key factor for the pathological damage in diabetic nephropathy. Interleukin -10 (IL-10) is a potent anti-inflammatory cytokines, which has the potential to reduce the pathological damage caused by inflammation in diabetic nephropathy. Due to a variety of technical difficulties, the attempt to use exogenous recombinant IL-10 protein as a therapy is not clinically successful. On the other hand, there is no applicable strategy to up-regulate the endogenous IL-10 expression yet. Our preliminary date showed that deacetylase HDAC6 functions as a negative regulator on the expression of endogenous IL-10. HDAC6 inhibitors specifically stimulates IL-10 production either in MMC (mouse mesangial cells) cultured in high glucose condition, or in MMC from mouse with diabetic nephropathy. Based on these results, we proposed that HDAC6 is a potential therapeutic target for the prevention of diabetic nephropathy, and hypothesize that inhibition of HDAC6 activity by drugs or genetic means will reduce inflammation and protect kidneys from pathological damage. The main objective of this project is to reveal the molecular mechanism of the HDAC6-dependent regulation on the expression of endogenous IL-10. Taking advantage of a variety of transgenic animal models and a patented method for drug target identification, we will investigate the efficacy and safety of HDAC6 inhibition for the clinical treatment of diabetic nephropathy, and provide scientific evidence for taking HDAC6 as a novel target against the disease.

炎症反应是糖尿病肾病造成病理性损伤的关键因素，白细胞介素-10（IL-10）作为高效的抗炎性细胞因子，能有效降低炎症反应造成的病理性损伤。目前将外源表达的重组IL-10蛋白用于临床并不成功，而人为调控内源性IL-10表达的方法仍未见报道。我们在前期研究中发现：去乙酰化酶HDAC6能够反向调控内源性IL-10的表达水平，HDAC6抑制剂能刺激高糖培养下小鼠肾小球系膜细胞（MMC）中IL-10特异性高表达，糖尿病肾病小鼠来源的MMC分泌IL-10也在HDAC6被抑制时升高。我们据此提出科学假设：HDAC6是预防糖尿病肾病的有效靶点，通过药物或基因手段抑制HDAC6的活力能够缓解炎症反应对肾脏造成的病理损伤。本课题的主要目标是解析HDAC6调控内源性IL-10表达水平的分子机理，同时考察调控HDAC6的活力在治疗糖尿病肾病中的有效性和安全性，为临床以HDAC6为靶点治疗糖尿病肾病提供科学依据。