Xin Wang, Bing Yao, Yinqiu Wang, Xiaofeng Fan, Suwan Wang, Aolei Niu, Haichun Yang, Agnes Fogo, Ming-Zhi Zhang, Raymond C Harris
Diabetic nephropathy (DN) is characterized by increased macrophage infiltration, and proinflammatory “M1” macrophages contribute to development of DN. Previous studies by us and others have reported that macrophage cyclooxygenase-2 (COX-2) plays a role in polarization and maintenance of a macrophage tissue reparative “M2” phenotype. We examined the effects of macrophage COX-2 on development of DN in type I diabetes. Cultured macrophages with COX-2 deletion exhibited an “M1” phenotype, as demonstrated by higher iNOS and NF-κB levels but lower IL-4Rα levels. Compared to corresponding wild type diabetic mice, mice with COX-2 deletion in hematopoietic cells (COX-2 knockout bone marrow transplantation) or macrophages (CD11b-Cre COX2f/f) developed severe DN, as indicated by increased albuminuria, fibrosis, and renal infiltration of T cells, neutrophils and macrophages. Although diabetic kidneys with macrophage COX-2 deletion had more macrophage infiltration, they had fewer renal “M2” macrophages. Diabetic kidneys with macrophage COX-2 deletion also had increased ER stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage EP4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/PGE2/EP4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.