Pex11a激动剂酪酸激活过氧化物酶体增殖与代谢治疗糖尿病肾病的分子机制

过氧化物酶体在慢性肾脏病发病过程中起重要作用。课题组的前期研究表明：Pex11a基因缺失导致肾小管细胞过氧化物酶体数量减少，代谢能力下降，进而脂肪、活性氧堆积，加重高血压肾损伤。酪酸能改善糖尿病肾病（DN）的肾功能，而其具体调控机制不明。预实验发现：Pex11a敲除加重DN，而酪酸诱导Pex11a表达、过氧化物酶体增殖及改善DN。据此提出科学假设：Pex11a在DN发病过程中起重要作用，诱导Pex11a能有效促进过氧化物酶体增殖、提高脂肪酸代谢能力和调节自由基平衡，从而抑制肾小管脂肪和活性氧堆积、防治DN。本研究主要目标是阐明Pex11a在DN发病过程中的重要作用，并利用Pex11a激活剂酪酸激活过氧化物酶体防治DN的可行性及有效性，同时以多种动物模型为研究手段，通过动物、细胞实验解析激活Pex11a表达防治DN的分子机制，为临床通过激活过氧化物酶体系统防治DN提供理论基础和科学依据。

Peroxisomes play a crucial role in the pathogenic process of chronic kidney disease. Our previous studies indicated that Pex11a deficiency was associated with a reduction in the abundance of functional peroxisomes in proximal tubule cells, a decrease in fatty acid β-oxidation, an increase in lipid and reactive oxygen species accumulation, and aggravated tubulointerstitial lesions in hypertensive renal injury. Butyric acid is a short chain fatty acid that can ameliorate acute/chronic kidney diseases, ie. diabetic nephropathy (DN), and promote peroxisome proliferation via Pex11a activation. But the mechanism is unclear. In our preliminary studies, we found that Pex11a deficiency aggravated DN. But butyric acid induced Pex11a, increased the number of peroxisomes and ameliorated DN. Based on these findings, we hypothesize that Pex11a plays a crucial role in the pathogenic process of DN. Promotion of Pex11a-mediated peroxisome proliferation by utilization of Pex11a activator sodium butyrate can increase lipid metabolism, and inhibit the accumulation of fatty acid and reactive oxygen species in proximal tubule cells, resulting in prevention from DN. To test this hypothesis, three specific aims were proposed: 1) To define Pex11a plays a crucial role in the pathogenic process of DN; 2) To define butyrate prevention from DN; 3) To define the mechanism that butyric acid up-regulation of Pex11a and promotion of peroxisome proliferation to prevent from DN. The objective of this project is to verify the feasibility and efficacy of using Pex11a activator butyrate to protect against DN via Pex11a-mediated peroxisome proliferation, which will provide strongly scientific evidences for targeting Pex11a to prevent DN in clinics.