Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy.

Wang X, Yao B, Wang Y, Fan X, Wang S, Niu A, Yang H, Fogo A, Zhang MZ, Harris RC
Diabetes. 2017 66 (2): 494-504

PMID: 27815317 · PMCID: PMC5248989 · DOI:10.2337/db16-0773

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 1 diabetes. Cultured macrophages with COX-2 deletion exhibited an M1 phenotype, as demonstrated by higher inducible nitric oxide synthase and nuclear factor-κB levels but lower interleukin-4 receptor-α levels. Compared with corresponding wild-type diabetic mice, mice with COX-2 deletion in hematopoietic cells (COX-2 knockout bone marrow transplantation) or macrophages (CD11b-Cre COX2) 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 endoplasmic reticulum stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage PGE receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E/PGE receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.

© 2017 by the American Diabetes Association.

MeSH Terms (24)

Albuminuria Animals Cells, Cultured Cyclooxygenase 2 Diabetes Mellitus, Experimental Diabetes Mellitus, Type 1 Diabetic Nephropathies Fibrosis Immunoblotting Immunohistochemistry Kidney Macrophages Male Mice Mice, Knockout Neutrophil Infiltration Neutrophils NF-kappa B Nitric Oxide Synthase Type II Real-Time Polymerase Chain Reaction Receptors, Prostaglandin E Receptors, Prostaglandin E, EP4 Subtype Signal Transduction T-Lymphocytes

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