Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype

Abstract

Objective-Chronic kidney disease (CKD) amplifies atherosclerosis, which involves reninangiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferatoractivated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model.Methods-Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response.Results-UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharideinduced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change.Conclusion-Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype.

Pioglitazone alleviates inflammation in diabetic mice fed a high‐fat diet via inhibiting advanced glycation end‐product‐induced classical macrophage activation

“…PPARγ agonists ameliorate diabetic atherosclerosis not only through beneficial effects on glucose and lipid metabolism, but also through anti‐inflammatory and immunoregulatory activities. PIO has been shown to improve the imbalance of regulatory and effector T cells in a uremic murine model , to regulate macrophage phenotype in a renal‐injury murine model , to reduce plaque inflammation in a non‐diabetic ApoE −/− mice model and to reduce the proportion of M1 monocytes/macrophages with consequent improvement in circulatory M1/M2 imbalance in obese type 2 diabetic patients . Consistently, in the present study, PIO administration significantly decreased the higher proportion of peripheral M1 monocytes/macrophages and improved the M1/M2 imbalance in diabetic circumferences.…”

10,12 Conjugated Linoleic Acid-Driven Weight Loss Is Protective against Atherosclerosis in Mice and Is Associated with Alternative Macrophage Enrichment in Perivascular Adipose Tissue

“…The reduction of atherosclerosis by 10,12 CLA supplementation was also striking, given the increased macrophage content of those lesions. It has been previously reported that atherosclerosis regression in response to thiazolidinedione treatment occurs despite increased lesion macrophage content [ 34 ], which were identified as largely resident M2 macrophages. Moreover, it is becoming increasingly appreciated that M2 macrophages support lesion regression by resolving inflammation and promoting tissue remodeling [ 34 , 35 , 36 ].…”

“…It has been previously reported that atherosclerosis regression in response to thiazolidinedione treatment occurs despite increased lesion macrophage content [ 34 ], which were identified as largely resident M2 macrophages. Moreover, it is becoming increasingly appreciated that M2 macrophages support lesion regression by resolving inflammation and promoting tissue remodeling [ 34 , 35 , 36 ]. Mice deficient in transcription factors that are required for M2 polarization have accelerated atherosclerosis [ 37 ], while administering type-2 cytokines such as IL-4 to mice protects against atherosclerosis [ 38 ].…”

PPARγand the Innate Immune System Mediate the Resolution of Inflammation

“…TZDs also promote M2 macrophages in other disease states. Pioglitazone enhanced M2 polarization in atherosclerotic lesions, diet-induced obesity, and a model of insulin resistance [ 77 – 79 ]. Rosiglitazone likewise enhanced expression of Arg-1 and CD206 in peritoneal and adipose tissue macrophages and in an in vitro model of COPD [ 80 – 82 ].…”