IGFBP-5/TGF-β1-mediated crosstalk between endothelial and tubular epithelial cells promotes interstitial fibrosis

Abstract Background Renal fibrosis is a common pathological feature of chronic kidney disease (CKD), but its underlying mechanisms remain incompletely understood. Our previous study demonstrated that insulin-like growth factor-binding protein 5 (IGFBP-5) promotes glycolytic reprogramming in vascular endothelial cells (ECs) and exacerbates renal inflammation in diabetic kidney disease (DKD). Methods Human renal proximal tubular epithelial cells (HK-2) and human umbilical vein endothelial cells (HUVECs) were used. A co-culture system was employed to investigate endothelial cell–tubular epithelial cell (EC-TEC) crosstalk. Unilateral ureteral obstruction (UUO) and aristolochic acid nephropathy (ANN) models were established in wild-type (WT), global IGFBP-5−/−, and endothelial-specific Tie-2 Cre; IGFBP-5−/− mice. Expression levels of IGFBP-5, TGF-β1, and fibrosis markers were assessed to to investigate the role of IGFBP-5 in renal fibrogenesis. Results Serum IGFBP-5 levels were significantly elevated in patients with chronic kidney disease (CKD). Genetic ablation of IGFBP-5 attenuated renal fibrosis in murine models, demonstrating its critical role in fibrogenesis. IGFBP-5 was predominantly expressed in endothelial cells (ECs), and endothelial-specific deletion delayed renal fibrosis progression via suppression of the TGF-β1/Smad3 pathway. In vitro, endothelial-derived IGFBP-5 promoted a profibrotic phenotypic transformation in TECs through AKT-mediated phosphorylation of the TGF-β1/Smad3 axis. Conversely, TGF-β1 stimulated IGFBP-5 biosynthesis and secretion in ECs via the ERK signaling pathway, establishing a self-amplifying feedback loop. This reciprocal IGFBP-5/TGF-β1 crosstalk between ECs and TECs was confirmed in co-culture experiments. Conclusion Our findings reveal a novel endothelial cell–tubular epithelial cell (EC-TEC) crosstalk axis mediated by reciprocal IGFBP-5/TGF-β1 signaling, which is a critical driver of renal fibrosis. IGFBP-5 emerges as a promising therapeutic target for inhibiting renal fibrogenesis in CKD.