Effect of bradykinin on TGF-β1-induced retinal pigment epithelial cell proliferation and extracellular matrix secretion

Abstract

BackgroundTo evaluate the effect of bradykinin (BK) on TGF-β1-induced retinal pigment epithelial (RPE) cell proliferation and extracellular matrix secretion and to elucidate the relationship between BK and the Erk/Akt signaling pathway.MethodsThe effects of BK on TGF-β1-induced RPE cell proliferation were examined via CCK-8 assay. Cell culture supernatant collagen I concentrations were measured via ELISA. Fibronectin (Fn), matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA and protein expression levels were measured via q-PCR and Western blotting, respectively. Changes in Akt/Erk phosphorylation induced by BK and HOE-140 were evaluated via Western blotting.ResultsTGF-β1 stimulated ARPE-19 cell proliferation, which was inhibited by BK, whose effects were inhibited by HOE-140. BK inhibited TGF-β1-induced collagen I, Fn and MMP-2 secretion in RPE cells, and these effects were inhibited by HOE-140. BK also inhibited TGF-β1-induced Akt phosphorylation in RPE cells, and these effects were blocked by HOE-140. BK had no significant effect on Erk-mediated signaling.ConclusionsThe findings from this study indicate that BK could be novel therapeutic targets for the treatment of PVR.

Roles of Drug Transporters in Blood-Retinal Barrier

“…These effects were reversed by NO synthase inhibitor L-NAME, vasoinhibins, and N-acetyl cysteine (Arredondo Zamarripa et al 2014). Bradykinin could also inhibit TGF-β1-stimulated ARPE-19 cell proliferation, collagen I, fibronectin, and MMP-2 secretion as well as Akt phosphorylation via activating bradykinin receptor 2 (Cai et al 2016). In normal rats, bradykinin-induced vasodilatation was involved in intracellular Ca2 + mobilization and products of the cyclooxygenase-2 (COX-2) pathway, but in STZ-diabetic rats, the vasodilatation in response to des-Arg9-bradykinin was involved in both calcium influx and intracellular calcium mobilization, which was blocked by GdCl 3 , 2,5-di-tbutylhydroquinone, and cADP ribose (Abdouh et al 2003).…”

Gremlin mediates the TGF‑β‑induced induction of profibrogenic genes in human retinal pigment epithelial cells

“…Elevated TGF-β levels have been reported in the subretinal fluids, vitreous and epiretinal membranes of patients with PVR (27)(28)(29)(30). TGF-β serves a vital role in PVR formation since it regulates cell proliferation, enhances ECM protein synthesis and induces ECM deposition (23,31). It has been previously demonstrated that the inhibition of TGF-β expression may prevent PVR progression (32).…”

Quercetin inhibits transforming growth factor β1-induced epithelial–mesenchymal transition in human retinal pigment epithelial cells via the Smad pathway

“…Some studies have indicated that multiple growth factors and cytokines are involved in the vitreous body of PVR patients, including tumor necrosis factor-α, interleukin-(IL-) 6, transforming growth factor-beta (TGF-β) and epidermal growth factor (EGF) 4. In our previous studies, TGF-β1 was found to have an essential role in EMT in RPE cell lines (ARPE-19) 5,6. TGF-β1-induced EMT triggers epithelial cells to alter their epithelial phenotype to one with mesenchymal characteristics, and the proliferation, migration, and collagen generation of TGF-β1-induced RPE cells are enhanced, accelerating EMT progression.…”