Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy.
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 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 endoplasmic reticulum stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage PGE2receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E2/PGE2receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.|Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Xin
X
Wang
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Bing
B
Yao
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Yinqiu
Y
Wang
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Xiaofeng
X
Fan
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Suwan
S
Wang
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Aolei
A
Niu
Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN.
Haichun
H
Yang
Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN.|Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, TN.
Agnes
A
Fogo
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN ray.harris@vanderbilt.edu ming-zhi.zhang@vanderbilt.edu.|Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, TN.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN.
Ming-Zhi
MZ
Zhang
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN ray.harris@vanderbilt.edu ming-zhi.zhang@vanderbilt.edu.|Vanderbilt Center for Kidney Disease, Vanderbilt University School of Medicine, Nashville, TN.|Nashville Veterans Affairs Hospital, Nashville, TN.
Raymond C
RC
Harris
D000419:Albuminuria; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D003928:Diabetic Nephropathies / Q000276:immunology*; D005355:Fibrosis; D015151:Immunoblotting; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D018078:Receptors, Prostaglandin E / Q000276:immunology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D016328:NF-kappa B; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2