Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis.

Abstract

Renal fibrosis serves as a critical pathological mechanism driving the progression of chronic kidney disease (CKD). However, the pathogenesis and therapeutic targets involved in this process remain unclear. Interestingly, we currently found that IGFBP7 is highly expressed in tubular epithelial cells (TECs) from the fibrotic kidneys of human patients and animal models. However, their functional roles in abnormal kidney repair and renal fibrosis remain unclear. Here, we report that IGFBP7 knockout (KO) or TEC conditional KO (cKO) attenuated renal fibrosis in multiple mouse models, whereas IGFBP7 knock-in or restoration in IGFBP7-KO mice enhanced renal fibrosis. These in vivo findings were verified using cultured TECs and organoids generated from IGFBP7-cKO mice. Mechanistically, we found that IGFBP7 bound to pyruvate kinase M2 (PKM2) to promote the acetylation of PKM2 at the K433 site, thereby enhancing PKM2 dimerization and nuclear translocation, and subsequently accelerating lipid production and renal fibrosis via SREBP1-dependent mechanisms. Notably, through drug screening, we identified salmeterol (an asthma medication) as an IGFBP7 antagonist that effectively reduced fibrosis. Our findings reveal the IGFBP7/PKM2/SREBP1 axis as a central regulator of lipogenic fibrosis, offering genetic and pharmacological inhibition of IGFBP7 as promising therapeutic strategies for CKD.