Renal insulin-like growth factor binding-protein 7 is a critical promoter of progressive diabetic kidney disease

Abstract Renal tubulointerstitial abnormalities predict diabetic kidney disease (DKD) progression, and targeting them may prevent DKD. Insulin-like growth factor binding-protein 7 (IGFBP7) is expressed in renal tubular cells and is elevated in both blood and urine during the early stages of human diabetes, serving as a predictor of the rate of disease progression. We showed that tubule- and glomerular-specific IGFBP7 promotes DKD, with tubular-derived IGFBP7 disrupting the renal microenvironment. IGFBP7 impairs mitochondrial bioenergetics in tubular cells, causing lipid accumulation, cell cycle arrest, interstitial inflammation, fibrosis, and glomerulosclerosis. These findings were substantiated by transgenic overexpression and the specific deletion of IGFBP7 in type 1/2 DKD mice. Mechanistically, IGFBP7 interacts with STAT3, promoting its acetylation/dimerization and downregulating mitochondrial bioenergetics. Our study identified levomefolic acid as a novel inhibitor of IGFBP7 and demonstrated its efficacy in mitigating the progression of DKD. Here we showed IGFBP7 is a promising therapeutic target for DKD.