Peroxisome Proliferator e Activated Receptor a Protects Capillary Pericytes in the Retina
Peroxisome Proliferator e Activated Receptor a Protects Capillary Pericytes in the Retina
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周细胞变性是糖尿病视网膜病变的早期事件，并且在糖尿病视网膜病变的进展中发挥重要作用。临床研究表明，非诺贝特是一种过氧化物酶体增殖物激活受体 a (PPAR a) 激动剂，对 2 型糖尿病患者的糖尿病视网膜病变具有强大的治疗作用。我们评估了 PPAR a 对糖尿病视网膜病变周细胞损失的保护作用。在链脲佐菌素诱导的糖尿病小鼠中，非诺贝特治疗显着改善了视网膜脱细胞毛细血管的形成和周细胞损失。相反，与糖尿病野生型小鼠相比，PPAR a (cid:2) / (cid:2) 糖尿病小鼠出现更严重的视网膜脱细胞毛细血管形成和周细胞脱落。此外，PPAR a 敲除消除了非诺贝特对糖尿病引起的视网膜周细胞损失的保护作用。在培养的原代人视网膜毛细血管周细胞中，PPAR a 的激活和表达均显着减少了氧化应激诱导的细胞凋亡，减少了活性氧的产生，并通过阻断 NF-k B 激活下调了 NAD(P)H 氧化酶 4 的表达。此外，PPAR a 的激活和表达均减弱了氧化剂诱导的人视网膜毛细血管周细胞中线粒体O 2 消耗的抑制。与相同氧化应激下的野生型小鼠相比，PPAR a (cid:2) / (cid:2) 小鼠的原代视网膜周细胞显示出更多的细胞凋亡。这些发现确定了 PPAR a 对视网膜周细胞的保护作用，这是视网膜内源性 PPAR a 的一种新功能。 （美国病理学杂志 2014 年，184：2709 和 2720；http://dx.doi.org/10.1016/j.ajpath.2014.06.021）
Pericyte degeneration is an early event in diabetic retinopathy and plays an important role in progression of diabetic retinopathy. Clinical studies have shown that feno fi brate, a peroxisome proliferator e activated receptor a (PPAR a ) agonist, has robust therapeutic effects on diabetic retinopathy in type 2 diabetic patients. We evaluated the protective effect of PPAR a against pericyte loss in diabetic retinopathy. In streptozotocin-induced diabetic mice, feno fi brate treatment signi fi cantly ameliorated retinal acellular capillary formation and pericyte loss. In contrast, PPAR a (cid:2) / (cid:2) mice with diabetes developed more severe retinal acellular capillary formation and pericyte dropout, compared with diabetic wild-type mice. Furthermore, PPAR a knockout abolished the protective effect of feno- fi brate against diabetes-induced retinal pericyte loss. In cultured primary human retinal capillary pericytes, activation and expression of PPAR a both signi fi cantly reduced oxidative stress e induced apoptosis, decreased reactive oxygen species production, and down-regulated NAD(P)H oxidase 4 expression through blockade of NF- k B activation. Furthermore, activation and expression of PPAR a both attenuated the oxidant-induced suppression of mitochondrial O 2 consumption in human retinal capillary pericytes. Primary retinal pericytes from PPAR a (cid:2) / (cid:2) mice displayed more apoptosis, compared with those from wild-type mice under the same oxidative stress. These fi ndings identi fi ed a protective effect of PPAR a on retinal pericytes, a novel function of endogenous PPAR a in the retina. (Am J Pathol 2014, 184: 2709 e 2720; http://dx.doi.org/10.1016/j.ajpath.2014.06.021)