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Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy
- Source :
- Diabetes
- Publication Year :
- 2016
- Publisher :
- American Diabetes Association, 2016.
-
Abstract
- 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 PGE2 receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E2/PGE2 receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.
- Subjects :
- Male
0301 basic medicine
Complications
Neutrophils
T-Lymphocytes
Endocrinology, Diabetes and Metabolism
Prostaglandin E2 receptor
Immunoblotting
Nitric Oxide Synthase Type II
Biology
Kidney
Real-Time Polymerase Chain Reaction
Diabetes Mellitus, Experimental
Proinflammatory cytokine
Diabetic nephropathy
Mice
03 medical and health sciences
0302 clinical medicine
Fibrosis
Internal Medicine
medicine
Albuminuria
Animals
Receptors, Prostaglandin E
Diabetic Nephropathies
Prostaglandin E2
Receptor
Cells, Cultured
Mice, Knockout
Macrophages
NF-kappa B
Kidney metabolism
medicine.disease
Immunohistochemistry
3. Good health
Haematopoiesis
Diabetes Mellitus, Type 1
030104 developmental biology
Neutrophil Infiltration
Cyclooxygenase 2
030220 oncology & carcinogenesis
Immunology
Cancer research
Receptors, Prostaglandin E, EP4 Subtype
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 1939327X and 00121797
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....f579ed8c2e406239e182da9ad4644d1c