辣椒素通过抑制 poldip2 诱导的氧化应激改善糖尿病视网膜病变。
Capsaicin ameliorates diabetic retinopathy by inhibiting poldip2-induced oxidative stress.
机构信息
Department of Ophthalmology, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, 230601, China.
Department of Humanistic Medicine, School of Humanistic Medicine, Anhui Medical University, Hefei, Anhui, 230032, China.
出版信息
Redox Biol. 2022 Oct;56:102460. doi: 10.1016/j.redox.2022.102460. Epub 2022 Sep 3.
BACKGROUND
Oxidative stress and the resultant hyperpermeability play a vital role in the pathogenesis of diabetic retinopathy (DR). Poldip2 has been implicated in HO production, but the effects of capsaicin on poldip2 have not been reported.
METHODS
Diabetic Sprague-Dawley (SD) rats induced with STZ were treated with capsaicin or AAV-poldip2-shRNA, and human retinal microvascular endothelial cells (HRMECs) were treated with capsaicin or poldip2 siRNA.
RESULTS
Current data indicated that the expression of PPARγ, poldip2, Nox4, VCAM-1, HIF-1α, and VEGF increased in rat retinas with DR and in HRMECs treated with high glucose. The production of ROS or HO in the tissues, serum, and cells increased, and the paracellular permeability of cultured HRMECs with high glucose significantly increased. In addition, overt hyperpermeability of retinal microvessels and increased retinal neovascularization in diabetic rats were observed. However, capsaicin treatment inhibited these increases and suppressed the expression of PPARγ by enhancing its phosphorylation and ubiquitination in the retinas of DR rats. Poldip2 knockdown in HRMECs or its silencing in the retina of DR rats concomitantly led to reduced levels of Nox4, VCAM-1, HIF-1α, VEGF, ROS, and HO, and the paracellular permeability of HRMECs or the hyperpermeability of retinal microvessels in diabetic rat retinas decreased. Similarly, after PPARγ knockdown in HRMECs, poldip2, Nox4, HIF-1α, VEGF, ROS, and HO decreased, and the monolayer paracellular permeability was reduced accordingly.
CONCLUSION
Capsaicin may ameliorate diabetic retinopathy by activating TRPV1 and suppressing the PPARγ-poldip2-Nox4 pathway.
背景
氧化应激和由此产生的高通透性在糖尿病性视网膜病变（DR）的发病机制中起着至关重要的作用。Poldip2 已被牵连到 HO 的产生中，但尚未有关于辣椒素对 poldip2 的影响的报道。
方法
用 STZ 诱导糖尿病 Sprague-Dawley（SD）大鼠，用辣椒素或 AAV-poldip2-shRNA 处理，用人视网膜微血管内皮细胞（HRMEC）用辣椒素或 poldip2 siRNA 处理。
结果
目前的数据表明，DR 大鼠视网膜和高糖处理的 HRMEC 中 PPARγ、poldip2、Nox4、VCAM-1、HIF-1α 和 VEGF 的表达增加。组织、血清和细胞中 ROS 或 HO 的产生增加，高糖培养的 HRMEC 的细胞旁通透性显著增加。此外，还观察到糖尿病大鼠视网膜微血管明显通透性增加和新生血管形成增加。然而，辣椒素治疗通过增强 DR 大鼠视网膜中 PPARγ 的磷酸化和泛素化来抑制这些增加，并抑制 PPARγ 的表达。HRMEC 中的 poldip2 敲低或 DR 大鼠视网膜中的 poldip2 沉默，同时导致 Nox4、VCAM-1、HIF-1α、VEGF、ROS 和 HO 的水平降低，以及 HRMEC 的细胞旁通透性或糖尿病大鼠视网膜中微血管的高通透性降低。同样，在 HRMEC 中敲低 PPARγ 后，poldip2、Nox4、HIF-1α、VEGF、ROS 和 HO 减少，单层细胞旁通透性相应降低。
结论
辣椒素可能通过激活 TRPV1 并抑制 PPARγ-poldip2-Nox4 途径来改善糖尿病性视网膜病变。
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