biostudies-literatureDu LInnovation Plan for Postgraduates of Jiangsu ProvinceNational Natural Science Foundation of ChinaNatural Science Foundation of the Jiangsu Higher Education Institutions of Chinae2407462https://www.ebi.ac.uk/biostudies/studies/S-EPMC12005803biostudies-literatureUnknown12(15)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.Advanced science (Weinheim, Baden-Wurttemberg, Germany)GABP Promotes Mesangial Cell Proliferation and Renal Fibrosis Through GLI1 in Diabetic Nephropathy.PMC120058038200382281973377KYCX19_225220KJB31002282073906Yin XHu YZhang JLu YLiu SYang QRen DYang TDu LYu XLu QMing JfalseGABP Promotes Mesangial Cell Proliferation and Renal Fibrosis Through GLI1 in Diabetic Nephropathy.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.2025-01-01T00:00:00Z2025 Apr2025-07-03T03:04:32.142Z2025-07-03T03:04:32.142ZS-EPMC120058033998538110.1002/advs.202407462