Overexpressed Poldip2 Incurs Retinal Fibrosis via the TGF-β1/SMAD3 Signaling Pathway in Diabetic Retinopathy.

Retinal fibrosis is one of the major features of diabetic retinopathy (DR). Our recent research has shown that Poldip2 can affect early DR through oxidative stress, but whether Poldip2 would regulate retinal fibrosis during DR development is still enigmatic. Here, diabetic Sprague-Dawley (SD) rats were induced with streptozotocin (STZ) and treated with adeno-associated virus serotype 9–polymerase-δ interacting protein 2 (Poldip2) shRNA, while human adult retinal pigment epithelial (ARPE-19) cells were treated with high glucose or Poldip2 siRNA. We identified that in STZ-induced DR rats and ARPE-19 cells treated with high glucose, the expression of Poldip2, transforming growth factor-β1 (TGF-β1), phosphorylated-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, facilitates its nuclear translocation through interacting with it, and significantly enhances the expression of fibrosis makers. Collectively, Poldip2 was identified is a novel regulator of DR fibrosis and is expected to become a therapeutic target for PDR. Article Highlights: To investigate the role of polymerase-δ interacting protein 2 (Poldip2) in retinal fibrosis during diabetic retinopathy (DR) development. Does Poldip2 regulate retinal fibrosis in DR, and what are the underlying mechanisms? Poldip2 upregulation in DR correlates with increased expression of fibrotic markers, while Poldip2 deletion inhibits the transforming growth factor-β1/SMAD3 pathway, reducing fibrosis-related protein levels. Poldip2 emerges as a novel regulator of DR fibrosis, suggesting therapeutic potential for treating proliferative diabetic retinopathy. [ABSTRACT FROM AUTHOR]