Moritz Robert J, LeBaron Richard G, Phelix Clyde F, Rupaimoole Rajesha, Kim Hong Seok, Tsin Andrew, Asmis Reto
Department of Biology, University of Texas at San Antonio, San Antonio, USA.
Departments of Biochemistry and Clinical Laboratory Sciences, School of Health Professions, University of Texas Health Science Center at San Antonio, San Antonio, USA.
Int J Clin Med. 2016 Jul;7(7):496-510. doi: 10.4236/ijcm.2016.77055. Epub 2016 Jul 21.
Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF-1 that promote the synthesis of various ECM molecules. TGF-1 strongly enhances the expression of the gene 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-1, 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-1 antibody and TGF-1 receptor chemical antagonist blocked macrophage-induced apoptosis. BIGH3 antibody completely blocked apoptosis that was induced by TGF-1, and blocked apoptosis induced by exogenous recombinant BIGH3. These results uncover a distinctive interplay of macrophage-derived TGF-1, BIGH3 protein, and apoptosis, and indicate that BIGH3 is central in a novel pathway that promotes diabetic nephropathy. Macrophage TGF-1 and BIGH3 are identified as prediabetic biomarkers, and potential therapeutic targets for intervention in prediabetic and diabetic individuals.
代谢应激的肾脏部分特征在于有浸润的巨噬细胞和巨噬细胞衍生的TGF-1，它们促进各种细胞外基质（ECM）分子的合成。TGF-1强烈增强编码一种细胞粘附类、促凋亡ECM蛋白BIGH3的基因的表达。我们假设在糖尿病环境中，浸润的巨噬细胞、巨噬细胞衍生的TGF-1和BIGH3蛋白之间的关系会促进肾细胞死亡。为了研究这一假设，我们使用了我们的糖尿病并发症小鼠模型。高脂饮食的小鼠出现高胆固醇血症，而链脲佐菌素使高胆固醇血症小鼠患糖尿病。免疫组织化学图像显示，高胆固醇血症和糖尿病小鼠肾皮质中的巨噬细胞浸润和BIGH3蛋白增加。巨噬细胞使BIGH3表达增加两倍，肾近端小管上皮细胞凋亡增加86%。TGF-1抗体和TGF-1受体化学拮抗剂可阻断巨噬细胞诱导的凋亡。BIGH3抗体完全阻断了由TGF-1诱导的凋亡，并阻断了外源性重组BIGH3诱导的凋亡。这些结果揭示了巨噬细胞衍生的TGF-1、BIGH3蛋白和凋亡之间独特的相互作用，并表明BIGH3在促进糖尿病肾病的新途径中起核心作用。巨噬细胞TGF-1和BIGH3被确定为糖尿病前期生物标志物，以及糖尿病前期和糖尿病个体干预的潜在治疗靶点。
