Abstract
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.
Highlights
Advances in clinical treatments and strong emphasis on diabetes education have played significant roles in prediabetic and diabetic health care management
It is known that macrophages infiltrate diabetic kidney cortex, and that macrophage-derived TGF-β1 promotes ECM accumulation in diabetic cortical interstitium and basal lamina [28] [29]
TGF-β1 strongly upregulates expression of the BIGH3 gene, a logical expectation is that a greater quantity of macrophages and BIGH3 protein would be evident in kidney cortex of diabetic mice when compared to non-diabetic kidney cortex
Summary
Advances in clinical treatments and strong emphasis on diabetes education have played significant roles in prediabetic and diabetic health care management. Development of diabetic nephropathy generally involves monocyte/macrophage infiltration, an increase in the local production of cytokines and reactive oxygen species (ROS), increased apoptosis, and accumulation of ECM molecules. The latter is explained, in part, by cytokine-induced changes in the expression of genes that encode for the ECM molecules fibronectin, collagen types I and IV, laminin and proteoglycans [2]-[4]. The C-terminal portion of the 69-kDa BIGH3 becomes cleaved, yielding a stable 60-kDa BIGH3 protein, and generating C-terminally derived integrin-ligand peptides that appear to act as competitive inhibitors of the pro-survival ECM-integrin interactions [7]-[9] These BIGH3-derived C-terminal peptides induce apoptosis, giving rise to the term BMA (BIGH3-mediated apoptosis), which we use in this study. Several different laboratories have reported BMA on retinal pericytes [10], retinal endothelial cells [11] the osteosarcoma cell lines MG-63 and Saos-2 [9], transformed corneal epithelial cells [12], Chinese hamster ovary cells, and other cell types [8], the rationale to classify BIGH3 as a proapoptotic ECM protein
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