Klotho restoration by epigenetic intervention prevents renal fibrosis / 医学研究生学报

ABSTRACT

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 DNMT3a 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 DNMT1/3a 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.