Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease
Swayam Prakash Srivastava, Han Zhou, Rachel Shenoi, Myshal Morris, Begoña Lainez, Leigh Goedeke, Barani Kumar Rajendran, Ocean Setia, Binod Aryal, Keizo Kanasaki, Daisuke Koya, Ken Inoki, Alan Dardik, Thomas Bell, Carlos Fernández‐Hernando, Gerald I. Shulman, Julie E. Goodwin
Abstract
Angiopoietin-like 4 (ANGPTL4), a key protein involved in lipoprotein metabolism, has diverse effects. There is an association between Angptl4 and diabetic kidney disease; however, this association has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in stimulator of interferon genes pathway activation, expression of pro-inflammatory cytokines, reduced epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, lessened mitochondrial damage, and increased fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Angptl4 interacts with Integrin β1 and influences the association between dipeptidyl-4 with Integrin β1. We demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the kidneys and protects diabetic kidneys from proteinuria and fibrosis. Together, these data demonstrate that podocyte- and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.