GABP Promotes Mesangial Cell Proliferation and Renal Fibrosis Through GLI1 in Diabetic Nephropathy

Abstract Abnormal proliferation of mesangial cells is a hallmark of diabetic nephropathy (DN). However, the cellular signaling mechanisms that regulate this proliferation remain poorly understood. In this study, it is demonstrated that GA‐binding protein (GABP), a member of the ETS family of transcription factors composed of GABPα and GABPβ, plays a significant role in the development of renal fibrosis by modulating mesangial cell proliferation. Notably, the deficiency of GABP in mesangial cells inhibits hyperglycemia‐induced proliferation and mitigates renal fibrosis in a murine model of type 2 diabetes mellitus (T2DM). RNA sequencing analysis identifies GLI Family Zinc Finger 1 (GLI1) as the principal downstream effector of GABP in diabetic mice, serving as a crucial regulator of the G1/S transition within the cell cycle. Subsequent investigations have demonstrated that GABP interacts with the GLI1 promoter, facilitating mesangial cell proliferation via GLI1‐dependent pathways. This is evidenced by the fact that GLI1 knockdown abrogates the proliferation of mesangial cells with GABP overexpression. Consequently, GABP emerges as a pivotal regulator of renal fibrosis and represents a promising therapeutic target for the treatment of diabetic nephropathy.