Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy

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.

Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control

“…Our previous studies indicated that GPR40 is expressed in the mouse kidney, with the highest expression in the cortex and outer stripe of the outer medulla, and is most highly expressed in the epithelia (10). In contrast, GPR84 is abundantly found in monocytes/macrophages, granulocytes, and neutrophils, and it has been reported to mediate inflammatory cell activation (5,15,23). It is notable that there was markedly decreased inflammatory infiltrate following PBI-4050 treatment in renal tissue of both models of kidney injury.…”

“…In our initial studies, we treated mice with either vehicle or PBI-4050 (100 mg/kg) by daily gavage from 8-20 weeks of age. eNOS -/db/ db mice are moderately hypertensive (14,15), and PBI-4050 had no effect on blood pressure (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.120365DS1). In addition, there was no effect on body weight with PBI-4050 administration compared with vehicle-treated mice (Supplemental Figure 1B).…”

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

“…The relevance of M1 to the development of DN has been shown using mice with Mϕ cyclooxygenase-2 (Cox-2) deletion. These mice demonstrate increased M1 polarization, which is associated with increased renal injury [69]. Although other authors found that Mϕ in the kidneys of streptozotocin-induced DN rat are characterized by an elevated expression of galectin-3 and TGF-β, suggesting an M2 dominance [59].…”

Lymphatic Vessels Enhancing Adaptive Immunity Deteriorates Renal Inflammation and Renal Fibrosis

“…For example, macrophages consist of two subtypes, the pro-inflammatory M1 type and an anti-inflammatory M2 type. It has been reported that M1 type macrophages promote renal fibrosis requiring the presence of COX-2 [37]. Our research team sorted out Ly6C-macrophages in mice kidney at 5 days after IR operation and injected them under the renal capsule of mice with immune deficiency, finding that the original normal kidney showed damage and intrarenal fibrosis 5 days later, suggesting that Ly6C-macrophages directly damaged kidney and induced subsequent fibrosis [38].…”