摘要
肾脏纤维化是慢性肾脏病的特征性病理改变,临床缺乏有效治疗措施。肾脏特异抗衰老蛋白Klotho具有显著的抗肾脏纤维化作用,但在肾脏纤维化发生发展中受异常表观遗传修饰影响而持续下调,是防治肾脏纤维化的关键潜在靶点。笔者针对靶向干预Klotho缺失抗肾脏纤维化进行了一系列研究,首先确定了转化生长因子β(TGFβ)是导致肾脏纤维化Klotho下调的主要致病因子:TGF-β通过抑制miR-152和miR-30诱导DNA甲基化酶1/3a异常高表达,继而导致Klotho启动子超甲基化和Klotho沉默。接着发现中草药成分大黄酸和去乙酰化酶3(HDAC3)抑制剂能够分别通过抑制异常表达的DNA甲基化酶1/3a,缓解Klotho启动子超甲基化,及促进PPARγ240/265赖氨酸位点乙酰化修饰强化对Klotho的正向调控作用,进而恢复Klotho蛋白水平,并有效缓解肾脏纤维化及相关的慢性肾脏病和骨质病理损害。最终研究揭示了肾脏纤维化Klotho下调的表观遗传特征和有效干预策略,为重振Klotho治疗肾脏纤维化及相关疾病提供了新的设计思路。
Renal fibrosis is a pathological process presented in all chronic kidney diseases and lacks effective treatment. Renal anti-aging protein Klotho displays impressive anti-renal fibrosis capacities,but sustainedly depressed during the initiation and progression of renal fibrosis due to aberrant epigenetic modifications,making Klotho a potential target of epigenetic intervention in anti-renal fibrosis therapy. The author has performed a series of studies and first established TGFb as an essential upstream pathological factor that causes Klotho suppression by inhibiting miR-152 and miR-30. This inhibition subsequently induces DNMT1 and DNMT3 a and leads to Klothopromoter hypermethylation and Klotho suppression. Further,it has been found that Rhein from the Chinese medicinal herbal plant and a specific inhibitor of histone deacetylase（HDAC） 3 are capable of either inhibiting the aberrant DNMT1/3 a induction and Klotho promoter DNA hypermethylation or enhancing PPARg acetylationat lysine 240/265 and its up-regulation of Klotho,resulting in Klotho restoration and reduced renal fibrosis and the associated renal and bone injuries. Therefore our findings have revealed the distinct epigenetic features of Klotho suppression in renal fibrosis and demonstrated the promising potentials of Klotho-targeted strategies in the treatment of renal fibrosis and the related disorders.
作者
曹望森
CAO Wang-sen(Basic Medical Science,Nanjing University School of Medicine,Nanjing 210093,Jiangsu,China)
出处
《医学研究生学报》
CAS
北大核心
2018年第7期673-677,共5页
Journal of Medical Postgraduates
基金
国家自然科学基金(81670672
81470940)
