Macrophage TGF-β1 and the Proapoptotic Extracellular Matrix Protein BIGH3 Induce Renal Cell Apoptosis in Prediabetic and Diabetic Conditions

Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF-β1 that promote the synthesis of various ECM molecules. TGF-β1 strongly enhances the expression of the gene TGFBI that encodes a cell-adhesion class, proapoptotic ECM protein called BIGH3. We hypothesized that in a diabetic environment a relationship between infiltrating macrophages, macrophage-derived TGF-β1, and BIGH3 protein promotes renal cell death. To investigate this hypothesis, we used our mouse model of diabetic complications. Mice on a high-fat diet developed hypercholesterolemia, and exposure to streptozotocin rendered hypercholesterolemic mice diabetic. Immunohistochemical images show increased macrophage infiltration and BIGH3 protein in the kidney cortices of hypercholesterolemic and diabetic mice. Macrophages induced a two-fold increase in BIGH3 expression and an 86% increase in renal proximal tubule epithelial cell apoptosis. TGF-β1 antibody and TGF-β1 receptor chemical antagonist blocked macrophage-induced apoptosis. BIGH3 antibody completely blocked apoptosis that was induced by TGF-β1, and blocked apoptosis induced by exogenous recombinant BIGH3. These results uncover a distinctive interplay of macrophage-derived TGF-β1, BIGH3 protein, and apoptosis, and indicate that BIGH3 is central in a novel pathway that promotes diabetic nephropathy. Macrophage TGF-β1 and BIGH3 are identified as prediabetic biomarkers, and potential therapeutic targets for intervention in prediabetic and diabetic individuals.