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Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.
PLoS One. 2015; 10(2):e0117757.Plos

Abstract

OBJECTIVE

This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.

METHODS

Eight-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.

RESULTS

HE 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).

CONCLUSION

Our results suggest that sorafenib may useful for the treatment of renal fibrosis through the suppression of TGF-β/Smad3-induced EMT signaling.

Authors+Show Affiliations

Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25679376

Citation

Jia, Lining, et al. "Sorafenib Ameliorates Renal Fibrosis Through Inhibition of TGF-β-induced Epithelial-mesenchymal Transition." PloS One, vol. 10, no. 2, 2015, pp. e0117757.
Jia L, Ma X, Gui B, et al. Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition. PLoS One. 2015;10(2):e0117757.
Jia, L., Ma, X., Gui, B., Ge, H., Wang, L., Ou, Y., Tian, L., Chen, Z., Duan, Z., Han, J., & Fu, R. (2015). Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition. PloS One, 10(2), e0117757. https://doi.org/10.1371/journal.pone.0117757
Jia L, et al. Sorafenib Ameliorates Renal Fibrosis Through Inhibition of TGF-β-induced Epithelial-mesenchymal Transition. PLoS One. 2015;10(2):e0117757. PubMed PMID: 25679376.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition. AU - Jia,Lining, AU - Ma,Xiaotao, AU - Gui,Baosong, AU - Ge,Heng, AU - Wang,Li, AU - Ou,Yan, AU - Tian,Lifang, AU - Chen,Zhao, AU - Duan,Zhaoyang, AU - Han,Jin, AU - Fu,Rongguo, Y1 - 2015/02/13/ PY - 2014/07/20/received PY - 2014/12/18/accepted PY - 2015/2/14/entrez PY - 2015/2/14/pubmed PY - 2016/4/30/medline SP - e0117757 EP - e0117757 JF - PloS one JO - PLoS One VL - 10 IS - 2 N2 - OBJECTIVE: This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect. METHODS: Eight-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. RESULTS: HE 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). CONCLUSION: Our results suggest that sorafenib may useful for the treatment of renal fibrosis through the suppression of TGF-β/Smad3-induced EMT signaling. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/25679376/Sorafenib_ameliorates_renal_fibrosis_through_inhibition_of_TGF_β_induced_epithelial_mesenchymal_transition_ L2 - https://dx.plos.org/10.1371/journal.pone.0117757 DB - PRIME DP - Unbound Medicine ER -