Klotho Prevented Epithelial-to-Mesenchymal Transition in High-Fat Diet/Streptozotocin-Induced Mice by Targeting NFkB/Microrna-21/Smad7 Signaling Pathway

Klotho is an antiaging hormone present in the kidney that protect renal via attenuating the nuclear factor-kB (NFkB) p65 activity. And in kidney epithelium miRNAs become active in response to injury. But little is known regarding to the role of Klotho on miRNAs in the pathogenesis of diabetic nephropathy(DN). In this study, we found that the expression of Klotho was reduced with upregulation of miR-21 and key parameters of DN in HFD/STZ-induced diabetic mice. Klotho-treatment reduced p65 nucleus expression in association with modulation of miR-21/Smad7 and amelioration of fibrosis. Furthermore, we found that Klotho expression was decreased in high glucose induced HK2 at both mRNA and protein, accompanied by the significantly increased miR-21 expression. NF-κB was demonstrated to regulate miR-21 expression by directly binding to its promotor. Additionally, exogenous addition of Klotho or inhibition of NF-kB restrained the activity of miR-21/Smad7 signaling pathways, which suppressed fibrosis in high glucose cultured HK2. This study provides a new basis to elucidate the protection mechanism of anti-aging protein Klotho in diabetic kidney. We firstly found that Klotho treatment could delay the fobrosis progression of diabetic nephropathy in type 2 diabetic mice via inhibition of NF-kB/miR-21/Smad7 signaling cascade pathways.