以Pex11a基因为靶点防治高血压肾损伤的分子机制

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 deoxycorticosterone acetate- and salt-induced hypertension model. Butyric acid is a short chain fatty acid that can ameliorate acute/chronic kidney diseases, ie. diabetic nephropathy, and promote peroxisome proliferation via Pex11a activation. In our preliminary studies, we found that butyric acid induced Pex11a, increased the number of peroxisomes and ameliorated hypertensive renal injury. Based on these findings, we hypothesize that Pex11a is a potential therapeutic approach to prevent hypertensive renal injury, promotion of Pex11a-mediated peroxisome proliferation by utilization of peroxisome proliferator butyric acid can increase lipid metabolism, and inhibit the accumulation of fatty acid and reactive oxygen species in proximal tubule cells, resulting in prevention of hypertensive renal injury. To test this hypothesis, three specific aims were proposed: 1) To define whether peroxisome proliferator butyric acid can prevent hypertensive renal injury in deoxycorticosterone acetate- and salt-induced hypertension and angiontensinⅡ-induced hypertension models; 2) To define the pivotal role of Pex11a in peroxisome proliferator butyric acid prevention from hypertensive renal injury; 3) To define the mechanism that butyric acid up-regulation of Pex11a and promotion of peroxisome proliferation to prevent hypertensive renal injury. The objective of this project is to verify the feasibility and efficacy of using a peroxisome proliferation activator butyric acid to protect against hypertensive renal injury via Pex11a-mediated peroxisome proliferation, which will provide strongly scientific evidences for targeting Pex11a to prevent hypertensive renal injury in clinics.

过氧化物酶体在慢性肾脏病发病过程中起着重要的作用。前期研究表明：Pex11a基因缺陷导致近端肾小管细胞过氧化物酶体数量减少，代谢能力下降，脂肪堆积，并加重高血压肾损伤。酪酸能改善急慢性肾脏病，并依赖Pex11a诱导细胞过氧化物酶体增殖。预实验发现：酪酸诱导Pex11a表达、过氧化物酶体增殖及改善高血压肾损伤。课题组据此提出科学假设：Pex11a可能是治疗高血压肾损伤的有效靶点，通过酪酸诱导Pex11a表达，促进过氧化物酶体增殖，提高代谢能力，抑制脂肪和活性氧堆积，防治高血压肾损伤。主要目标是考察以Pex11a为靶点、利用过氧化物酶体激活剂酪酸防治高血压肾损伤的可行性及有效性，同时以Pex11a-KO、Pex11a-TG、PPAR-α-KO等转基因动物模型为研究手段，解析酪酸上调Pex11a防治高血压肾损伤的分子机制，为将来临床以Pex11a为靶点防治高血压肾损伤提供理论基础和科学依据。

慢性肾脏病已成为继心脑血管疾病、肿瘤、糖尿病之后又一个威胁人类健康的重要疾病，但是其具体发病机制不明且防治手段有限。前期研究表明Pex11a在过氧化物酶体增殖、脂肪酸代谢及慢性肾脏病发病过程中起重要作用，而酪酸能诱导Pex11a表达。据此课题组提出科学假设：Pex11a可能是治疗高血压肾损伤的有效靶点，通过酪酸诱导Pex11a表达，促进过氧化物酶体增殖，提高脂肪酸代谢能力及调节自由基平衡，防治高血压肾损伤。主要目标是考察以Pex11a为靶点、利用过氧化物酶体激活剂酪酸防治高血压肾损伤的可行性及有效性，解析酪酸上调Pex11a防治高血压肾损伤的分子机制。为了实现以上目标，我们开展了以下实验：实验1，考察酪酸治疗高血压肾损伤的有效剂量；实验2，利用Pex11a-KO小鼠证实Pex11a在酪酸防治高血压肾损伤中的作用；实验3，利用Pex11a-Tg小鼠解析内源性Pex11a高表达对高血压肾损伤的保护作用；实验4，解析了Pex11a促进过氧化物酶体增殖的机制及Pex11a对过氧化物酶体代谢能力的影响。研究首先发现5%酪酸钠能显著地提高肾脏Pex11a表达及提高过氧化物酶体数量。本研究采用醋酸脱氧皮质酮（DOCA）诱导盐敏感性高血压小鼠模型模拟慢性肾脏病（高血压肾损伤），并发现给予模型动物含有5%酪酸钠的饲料能显著地抑制高血压肾损伤的尿白蛋白、β-N-乙酰氨基葡萄糖苷酶（NAG）及肾损伤。重要的是酪酸抑制尿白蛋白、NAG及肾损伤依赖Pex11a基因。我们也通过内源性提高Pex11a表达（Pex11a-Tg）发现高Pex11a表达促进过氧化物酶体伸长、分裂增殖，提高过氧化物酶体抗氧化能力，从而抑制高血压肾损伤的肾小管扩张、萎缩、坏死、纤维化及巨噬细胞浸润。以上结果表明以Pex11a为靶点，酪酸钠治疗盐敏感性高血压是现实可行的。为临床治疗盐敏感性高血压肾损伤提供崭新的干预策略。