A HGF‑derived peptide suppresses EMT in human lens epithelial cells via the TGF‑β/Smad and Akt/mTOR signaling pathways

Abstract

Posterior capsule opacification (PCO) as a result of proliferation and fibrogenesis of lens epithelial cells (LECs) is the most frequent long-term complication of modern cataract surgery. LECs may undergo epithelial-mesenchymal transition (EMT) that resembles the morphological and molecular characteristics of PCO. A pre-identified novel, hepatocyte growth factor (HGF)-derived peptide H-RN, was reported to exhibit anti-angiogenic activity and anti-inflammatory effects in ocular cells both in vitro and in vivo. However, the role of H-RN in the promotion of the development of EMT in LECs is unknown. In the present study, the effects of H-RN on the development of EMT induced by transforming growth factor (TGF)-β in human LECs, and the possible signaling pathways participating in this process were investigated. The results showed that H-RN promoted the expression of the EMT-associated markers, α-smooth muscle actin and fibronectin, whereas the expression of E-cadherin and connexin 43 were reduced. The morphological changes typically associated with EMT seen in LECs induced by TGF-β2 were inhibited by H-RN, which was consistent with the effects of a TGF-β2 inhibitor, SB431542. Smad2 and Smad3 phosphorylation induced by TGF-β2 were reduced by H-RN, and phosphorylation of Akt, mTOR and P70S6K induced by TGF-β2 were also notably reduced by H-RN in LECs. Therefore, the results of the present study showed that H-RN treatment significantly suppressed the development of EMT induced by TGF-β2, at least partially through the TGF-β/Smad and Akt/mTOR signaling pathways in human LECs. The present study highlights that H-RN, a novel HGF-derived peptide, may be a novel therapeutic agent for prevention and treatment of PCO.

Hepatocyte Growth Factor DNA Aptamer for Prevention of Postoperative Peritoneal Adhesion via Enhancement of Fibrinolysis and Inhibition of Mesothelial Mesenchymal Transition

“…This equilibrium is crucial because net plasminogen activity contributes to the degradation of excessive fibrin clots, preventing fibrin accumulation and further adhesion development. Previous reports have demonstrated that human recombinant HGF promotes the tPA expression while downregulating PAI-1 expression, leading to a higher net plasminogen activity. , Importantly, HGF has been found to hamper the Smad2/3 pathway by inducing the inhibitory messenger Smad7, suggesting that HGF is effective in regulating multiple Smad2/3-mediated events. , In this study, the HGF DNA aptamer effectively restored the elevated PAI-1 expression induced by TGF-β to the basal level, whereas it induced tPA expression above baseline compared to the control group. These results confirm the efficacy of the HGF DNA aptamer in promoting fibrinolytic activity, and the increase in tPA expression was consistent with the downregulation of PAI-1.…”

“…56,62 Importantly, HGF has been found to hamper the Smad2/3 pathway by inducing the inhibitory messenger Smad7, suggesting that HGF is effective in regulating multiple Smad2/3-mediated events. 55,63 In this study, the HGF DNA aptamer effectively restored the elevated PAI-1 expression induced by TGF-β to the basal level, whereas it induced tPA expression above baseline compared to the control group. These results confirm the efficacy of the HGF DNA aptamer in promoting fibrinolytic activity, and the increase in tPA expression was consistent with the downregulation of PAI-1.…”

Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways

“…Hepatocyte growth factor splice variant NK1 (HGF/NK1) and bone morphogenetic protein 7 (BMP7) are two growth factors with demonstrated potent anti-fibrotic activities [ 22 , 23 ]. Huang and colleagues [ 15 ] employed H-RN peptide, derived from the kringle 1 domain present in HGF/NK1, to show in vitro inhibition of TGF-β2/Smad2/3-dependent induction of epithelial-mesenchymal transition (EMT) in lens epithelial cells, preventing their acquisition of myofibroblastic markers. H-RN also prevented TGF-β2/Smad-independent activation of Akt, mTOR, and p70S6K.…”

Regulation of TGF-β2-induced epithelial-mesenchymal transition and autophagy in lens epithelial cells by the miR-492/<i>NPM1</i> axis

“…We found the TGF-β signalling pathway to be one of the primary pathways for NPM1 enrichment. This signalling system has been shown to have a function in the creation and maintenance of the eye lens (47,48). TGF-β family is critical for regulating cell differentiation and other physiological processes and its dysregulation is linked to developmental defects, illness, cancer, and fibrosis (49,50).…”