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Peroxisome proliferator-activated receptor ? protects capillary pericytes in the retina.

ABSTRACT: Pericyte degeneration is an early event in diabetic retinopathy and plays an important role in progression of diabetic retinopathy. Clinical studies have shown that fenofibrate, a peroxisome proliferator-activated receptor ? (PPAR?) agonist, has robust therapeutic effects on diabetic retinopathy in type 2 diabetic patients. We evaluated the protective effect of PPAR? against pericyte loss in diabetic retinopathy. In streptozotocin-induced diabetic mice, fenofibrate treatment significantly ameliorated retinal acellular capillary formation and pericyte loss. In contrast, PPAR?(-/-) mice with diabetes developed more severe retinal acellular capillary formation and pericyte dropout, compared with diabetic wild-type mice. Furthermore, PPAR? knockout abolished the protective effect of fenofibrate against diabetes-induced retinal pericyte loss. In cultured primary human retinal capillary pericytes, activation and expression of PPAR? both significantly reduced oxidative stress-induced apoptosis, decreased reactive oxygen species production, and down-regulated NAD(P)H oxidase 4 expression through blockade of NF-?B activation. Furthermore, activation and expression of PPAR? both attenuated the oxidant-induced suppression of mitochondrial O2 consumption in human retinal capillary pericytes. Primary retinal pericytes from PPAR?(-/-) mice displayed more apoptosis, compared with those from wild-type mice under the same oxidative stress. These findings identified a protective effect of PPAR? on retinal pericytes, a novel function of endogenous PPAR? in the retina.

SUBMITTER: Ding L

PROVIDER: S-EPMC4188867 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor α protects capillary pericytes in the retina.

Ding Lexi L Cheng Rui R Hu Yang Y Takahashi Yusuke Y Jenkins Alicia J AJ Keech Anthony C AC Humphries Kenneth M KM Gu Xiaowu X Elliott Michael H MH Xia Xiaobo X Ma Jian-Xing JX

The American journal of pathology 20140807 10

Pericyte degeneration is an early event in diabetic retinopathy and plays an important role in progression of diabetic retinopathy. Clinical studies have shown that fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has robust therapeutic effects on diabetic retinopathy in type 2 diabetic patients. We evaluated the protective effect of PPARα against pericyte loss in diabetic retinopathy. In streptozotocin-induced diabetic mice, fenofibrate treatment significantly amelio ...[more]

PMID: 25108226

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Project description:Peroxisome proliferator-activated receptor-? is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-? null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor-? in sepsis and to identify the mechanism whereby peroxisome proliferator-activated receptor-? confers a survival advantage.Prospective randomized preclinical study.Laboratory investigation.Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks.Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses.Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-? status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice.Peroxisome proliferator-activated receptor-? expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator-activated receptor-? expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara mice. These results suggest that altered peroxisome proliferator-activated receptor-?-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart.

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Peroxisome proliferator-activated receptor ? protects capillary pericytes in the retina.

Publications

Peroxisome proliferator-activated receptor α protects capillary pericytes in the retina.

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