Srivastava, S. P.; Zhou, H.; Shenoi, R.; Morris, M.; Goedeke, L.; Rajendran, B. K.; Setia, O.; Aryal, B.; Kanasaki, K.; Koya, D.; Dardik, A.; Bell, T.; Fernandez-Hernando, C.; Shulman, G.; Goodwin, J. E.

Angiopoietin-like 4 (ANGPTL4) is the key protein involved in lipoprotein metabolism and has been shown to have diverse effects on tissue protection. In clinical settings, there is a reported association between higher levels of plasma Angptl4 and features of diabetic kidney disease, however, the association between kidney Angptl4 with features of diabetic kidney disease has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Results from mRNA-array analysis in control (non-fibrotic) and diabetic (fibrotic) kidneys suggest time-dependent emergence of Angplt4 expression. 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 the levels of pro-inflammatory cytokines, epithelial-to-mesenchymal transition, endothelial-to-mesenchymal transition and augmented fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Angptl4 interacts with Integrin-beta1 and influences the association between dipeptidyl-4 with Integrin-beta1 and promotes heterodimerization of transforming growth factor-beta receptor 1 (TGFbetaR1) and TGFbetaR2 in cultured cells. This in turn results in Smad3 phosphorylation and subsequent downregulation of the expression of genes involved in fatty acid oxidation; these cumulative effects led to the activation of fibrogenic phenotypes. 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. Importantly, use of this kidney-specific targeted strategy is beneficial and does not cause any harmful effect suggesting it can be used as a novel drug molecule for treatment of diabetic kidney disease. Taken together, these data demonstrate that podocyte- and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.