Capsaicin ameliorates diabetic retinopathy by inhibiting poldip2-induced oxidative stress

Oxidative stress and the resultant hyperpermeability play a vital role in the pathogenesis of diabetic retinopathy (DR). Poldip2 has been implicated in H₂O₂ production, but the effects of capsaicin on poldip2 have not been reported.

Diabetic Sprague-Dawley (SD) rats induced with STZ were treated with capsaicin or AAV₉-poldip2-shRNA, and human retinal microvascular endothelial cells (HRMECs) were treated with capsaicin or poldip2 siRNA.

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 H₂O₂ 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 H₂O₂, 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 H₂O₂ decreased, and the monolayer paracellular permeability was reduced accordingly.

Capsaicin may ameliorate diabetic retinopathy by activating TRPV1 and suppressing the PPARγ-poldip2-Nox4 pathway.