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Cyclic helix B peptide inhibits ischemia reperfusion-induced renal fibrosis via the PI3K/Akt/FoxO3a pathway.

Yang C, Cao Y, Zhang Y, Li L, Xu M, Long Y, Rong R, Zhu T - J Transl Med (2015)

Bottom Line: Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function.We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects.Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. esuperyc@163.com.

ABSTRACT
Renal fibrosis is a main cause of end-stage renal disease. Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function. We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. In this study, we evaluated the effect of CHBP on renal fibrosis in an in vivo ischemia reperfusion injury (IRI) model and in vitro TGF-β-stimulated tubular epithelial cells (TCMK-1 and HK-2) model. In the IRI in vivo model, mice were randomly divided into sham (sham operation), IR and IR + CHBP groups (n = 6). CHBP (8 nmol/kg) was administered intraperitoneally at the onset of reperfusion, and renal fibrosis was evaluated at 12 weeks post-reperfusion. Our results showed that CHBP markedly attenuated the IRI-induced deposition of collagen I and vimentin. In the in vitro model, CHBP reversed the TGF-β-induced down-regulation of E-cadherin and up-regulation of α-SMA and vimentin. Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA. These findings demonstrate that CHBP attenuates renal fibrosis and the epithelial-mesenchymal transition of tubular cells, possibly through suppression of the PI3K/Akt pathway and thereby the inhibition FoxO3a activity.

No MeSH data available.


Related in: MedlinePlus

CHBP inhibited TGF-β-induced EMT in murine and human TECs. TGF-β (5 ng/ml) and CHBP (0, 0.1, 1 and 10 μM) were added to murine TCMK-1 and human HK-2 cells. After 72 h, E-cadherin, vimentin and α-SMA levels in a TCMK-1 cells and b HK-2 cells were determined by western blotting. c, d Quantitative results are presented as the mean ± SD of the optical density of each band (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with the CHBP (0 μM) + TGF-β (5 ng/ml) group
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Fig4: CHBP inhibited TGF-β-induced EMT in murine and human TECs. TGF-β (5 ng/ml) and CHBP (0, 0.1, 1 and 10 μM) were added to murine TCMK-1 and human HK-2 cells. After 72 h, E-cadherin, vimentin and α-SMA levels in a TCMK-1 cells and b HK-2 cells were determined by western blotting. c, d Quantitative results are presented as the mean ± SD of the optical density of each band (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with the CHBP (0 μM) + TGF-β (5 ng/ml) group

Mentions: The expression levels of E-cadherin, vimentin and a-SMA, all well-known markers of EMT, were analyzed in murine (Fig. 4a) and human (Fig. 4b) TECs using 5 ng/ml TGF-β. Western blotting analysis revealed that CHBP significantly inhibited the expression of a-SMA and vimentin and enhanced the expression of E-cadherin compared with the control groups in both murine (Fig. 4c) and human (Fig. 4d) TECs. The anti-EMT effects of CHBP were concentration-dependent.Fig. 4


Cyclic helix B peptide inhibits ischemia reperfusion-induced renal fibrosis via the PI3K/Akt/FoxO3a pathway.

Yang C, Cao Y, Zhang Y, Li L, Xu M, Long Y, Rong R, Zhu T - J Transl Med (2015)

CHBP inhibited TGF-β-induced EMT in murine and human TECs. TGF-β (5 ng/ml) and CHBP (0, 0.1, 1 and 10 μM) were added to murine TCMK-1 and human HK-2 cells. After 72 h, E-cadherin, vimentin and α-SMA levels in a TCMK-1 cells and b HK-2 cells were determined by western blotting. c, d Quantitative results are presented as the mean ± SD of the optical density of each band (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with the CHBP (0 μM) + TGF-β (5 ng/ml) group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4641348&req=5

Fig4: CHBP inhibited TGF-β-induced EMT in murine and human TECs. TGF-β (5 ng/ml) and CHBP (0, 0.1, 1 and 10 μM) were added to murine TCMK-1 and human HK-2 cells. After 72 h, E-cadherin, vimentin and α-SMA levels in a TCMK-1 cells and b HK-2 cells were determined by western blotting. c, d Quantitative results are presented as the mean ± SD of the optical density of each band (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with the CHBP (0 μM) + TGF-β (5 ng/ml) group
Mentions: The expression levels of E-cadherin, vimentin and a-SMA, all well-known markers of EMT, were analyzed in murine (Fig. 4a) and human (Fig. 4b) TECs using 5 ng/ml TGF-β. Western blotting analysis revealed that CHBP significantly inhibited the expression of a-SMA and vimentin and enhanced the expression of E-cadherin compared with the control groups in both murine (Fig. 4c) and human (Fig. 4d) TECs. The anti-EMT effects of CHBP were concentration-dependent.Fig. 4

Bottom Line: Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function.We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects.Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. esuperyc@163.com.

ABSTRACT
Renal fibrosis is a main cause of end-stage renal disease. Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function. We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. In this study, we evaluated the effect of CHBP on renal fibrosis in an in vivo ischemia reperfusion injury (IRI) model and in vitro TGF-β-stimulated tubular epithelial cells (TCMK-1 and HK-2) model. In the IRI in vivo model, mice were randomly divided into sham (sham operation), IR and IR + CHBP groups (n = 6). CHBP (8 nmol/kg) was administered intraperitoneally at the onset of reperfusion, and renal fibrosis was evaluated at 12 weeks post-reperfusion. Our results showed that CHBP markedly attenuated the IRI-induced deposition of collagen I and vimentin. In the in vitro model, CHBP reversed the TGF-β-induced down-regulation of E-cadherin and up-regulation of α-SMA and vimentin. Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA. These findings demonstrate that CHBP attenuates renal fibrosis and the epithelial-mesenchymal transition of tubular cells, possibly through suppression of the PI3K/Akt pathway and thereby the inhibition FoxO3a activity.

No MeSH data available.


Related in: MedlinePlus