Sorafenib Ameliorates Renal Fibrosis through Inhibition of TGF-β-Induced Epithelial-Mesenchymal Transition

Abstract

ObjectiveThis study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.MethodsEight-week-old rats were subjected to unilateral ureteral obstruction (UUO) and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis.ResultsHE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05). Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01). The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05). Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05). The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05). Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05).ConclusionOur results suggest that sorafenib may useful for the treatment of renal fibrosis through the suppression of TGF-β/Smad3-induced EMT signaling.

Transforming growth factor beta (TGF‐β) isoforms in wound healing and fibrosis

“…62 Further, the multi-kinase inhibitor sorafenib was shown to ameliorate experimentally induced renal fibrosis in a rat model, and this benefit was due to inhibition of TGF-b1signaling via Smad3. 63 Interestingly, EMT may also underlie skin fibrosis in systemic sclerosis, 64 suggesting that sorafenib, like fresolimumab, may also show benefit in skin sclerosis.…”

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

“…TGF-β1 is commonly used to induce EMT in a variety of cancer cell types (14,15). We therefore established a TGF-β1-dependent model of EMT for gastric cancer cell lines.…”

Adenovirus-mediated P311 ameliorates renal fibrosis through inhibition of epithelial-mesenchymal transition via TGF-β1-Smad-ILK pathway in unilateral ureteral obstruction rats

“…TGF-β1, a well-known master cytokine/growth factor, is considered as an important well-established regulator of EMT. It could effectively regulate the transdifferentiation of tubular epithelial cells into myofibroblasts in renal fibrosis primarily via Smad-dependent pathway (10,11). Upon TGF-β1 binding to its receptors, Serine/ Threonine kinases are activated and induce phosphorylation of Smad2/Smad3, then phosphorylated Smad2/3 partner with Smad4 translocate into the nucleus where they regulate the transcription of the target genes responsible for EMT (10).…”