PCSK9Qβ-003降脂疫苗抑制肾脏纤维化的机制研究

The incidence of chronic kidney disease (CKD) is increasing, while the current treatment measures are still very limited. Dyslipidemia is an important factor in promoting the progression of CKD. As an important molecule of lipid metabolism, PCSK9 is closely related to the prognosis of chronic kidney disease. We invented the PCSK9Qβ-003 vaccine. The vaccine can reduce LDL-C and inhibit renal fibrosis. Our further studies have found that PPARs are highly expressed in PCSK9Qβ-003 vaccine group, which can promote fatty acid oxidation. Based on this, we propose the hypothesis that PCSK9Qβ-003 vaccine can activate PPARs pathways and the downstream fatty acid oxidation-related signaling pathways, promote fatty acid oxidation in renal tubular epithelial cells (TECs) and Inhibit the phenotypic transformation of TECs. So as to slow down the process of renal fibrosis. The purpose of this study is to explore the relationship between PCSK9 and CKD, and to provide a new treatment for CKD.

慢性肾脏病（CKD）的发病率逐年增加，而治疗措施仍十分有限。血脂异常是促进CKD进展的重要因素。PCSK9作为血脂代谢的关键分子，与肾脏病预后密切相关。本课题组发明了PCSK9Qβ-003降脂疫苗。前期研究发现，该疫苗在降低LDL-C的同时，可以抑制肾脏纤维化。进一步的研究发现，该疫苗可以激活PPARs通路，从而促进脂肪酸氧化。基于此，我们提出本次研究假说：PCSK9Qβ-003疫苗发挥降脂效应的同时，激活肾小管上皮细胞内PPARs通路及其下游脂肪酸氧化相关信号分子，促进肾小管上皮细胞脂肪酸氧化，抑制其表型转化，从而延缓肾脏纤维化进程，改善慢性肾脏病的预后。进而探索PCSK9与CKD间的关系，为慢性肾病的治疗提供新的手段。

血脂异常在慢性肾脏疾病发生发展起重要作用。PCSK9作为血脂代谢的关键分子，与肾脏病预后密切相关。本课题组发现，PCSK9Qβ-003降脂疫苗在降低LDL-C的同时，可以抑制单侧输尿管结扎术（UUO）及eNOS抑制剂（L-NAME）诱导的肾脏纤维化。其主要机制如下：PCSK9Qβ-003降脂疫苗免疫机体后，上调肝脏脂肪酸代谢相关分子，激活肾小管上皮细胞内PPARs通路，促进其下游脂肪酸β氧化(FAO)相关分子表达，促进肾小管上皮细胞脂肪酸氧化，从而延缓肾脏纤维化进程，改善慢性肾脏病的预后。