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Overexpressed Poldip2 incurs retinal fibrosis via the TGFβ1/SMAD3 signaling pathway in diabetic retinopathy

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posted on 2024-07-05, 19:00 authored by Zhiyu Ji, Siyu Lin, Siyu Gui, Jie Gao, Fan Cao, Yiming Guan, Qinyu Ni, Keyang Chen, Liming Tao, Zhengxuan Jiang

Retinal fibrosis is one of the major features of Diabetic retinopathy. Our recent research has shown that Poldip2 can affect early DR through oxidative stress, but whether or not Poldip2 would regulate retinal fibrosis during DR development is still enigmatic. Here, Diabetic Sprague-Dawley (SD) rats were induced with STZ and treated with AAV9-Poldip2shRNA, while human retinal pigment epithelial cells (ARPE-19) were treated with high glucose (HG) or Poldip2 siRNA. We identified that in STZ-induced DR rats and ARPE-19 treated with high glucose, the expression of Poldip2, TGFβ1, P-SMAD3/SMAD3, MMP9, COL-1, FN, and CTGF increased while the expression of Cadherin decreased. However, deleting Poldip2 inhibited the TGF-β1/SMAD3 signaling pathway and attenuated the above protein expression in vivo and in vitro. Mechanistically, we found that Poldip2 promotes the activation of SMAD3, and facilitates its nuclear translocation through interacting with it, and significantly enhances the expression of fibrosis makers. Collectively, it was identified that Poldip2 is a novel regulator of DR fibrosis and it is expected to become a therapeutic target for PDR.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82371080, 82070986 and 82171043), the Natural Science Funds for Distinguished Young Scholar of Anhui Province (2308085J29 and 2023AH020046)

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