FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1.

Abstract

Diabetic nephropathy (DN) is one of the most important microvascular complications of diabetes. The role of epigenetic regulation in DN has attracted much attention recently. This research was performed to explore the role of FTO in the DN progression. The renal tissues of DN patients were collected and the podocytes were stimulated with high glucose (HG) to establish the DN model in vitro. Western blot along with reverse transcription quantitative polymerase chain reaction assays was performed to analyze the mRNA as well as protein expressions. Immunohistochemistry and immunofluorescence were carried out to measure the FTO and DACT1 levels. The interaction between FTO/IGF2BP1 and DACT1 was verified by double luciferase reports and RNA-binding protein immunoprecipitation assays. FTO was declined, and DACT1 was enhanced in the HG-treated podocytes as well as renal tissues of DN patients. Overexpressed FTO declined the mRNA levels of MCP-1, IL-6, TNF-α, and the apoptosis rate of HG-treated podocytes. The N6-methyladenosine (m6A) levels, mRNA expression, and stability of FTO were depleted after FTO overexpression. DACT1 overexpression reversed the function of oe-FTO in podocytes stimulated with HG. Furthermore, IGF2BP1 knockdown declined the mRNA expression as well as the stability of FTO. In conclusion, FTO-medicated m6A modification of DACT1 was dependent on IGF2BP1 in DN progression.