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P311 promotes renal fibrosis via TGFβ1/Smad signaling.

Yao Z, Yang S, He W, Li L, Xu R, Zhang X, Li H, Zhan R, Sun W, Tan J, Zhou J, Luo G, Wu J - Sci Rep (2015)

Bottom Line: We previously observed that P311 is highly expressed in skin hypertrophic scars.The interstitial deposition of collagen, α-SMA and TGF-β1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out.In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.

ABSTRACT
P311, a gene that was identified in 1993, has been found to have diverse biological functions in processes such as cell proliferation, migration and differentiation. However, its role in fibrosis is unknown. We previously observed that P311 is highly expressed in skin hypertrophic scars. In this study, P311 over-expression was detected in a subset of tubular epithelial cells in clinical biopsy specimens of renal fibrosis; this over-expression, was found concurrent with α-smooth muscle actin (α-SMA) and transforming growth factor beta1 (TGFβ1) expression. Subsequently, these results were verified in a mouse experimental renal fibrosis model induced by unilateral ureteral obstruction. The interstitial deposition of collagen, α-SMA and TGF-β1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out. Moreover, TGFβ/Smad signaling had a critical effect on the promotion of renal fibrosis by P311. In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis.

No MeSH data available.


Related in: MedlinePlus

P311 deficiency suppresses TGF-β1 expression in UUO mice.(A) RNA was isolated in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. TGF-β1 mRNA expression was determined by real-time PCR. (B) Representative photomicrographs of TGF-β1-specific immunohistochemical staining of UUO kidneys from P311+/+ and P311−/−mice on day 7. Black arrowhead indicates the TGF-β1-positive region. Bottom panel: negative controls for the immunohistochemical staining of TGF-β1 on the obstructed kidneys from both P311+/+ and P311−/− mice. (C) TGF-β1-positive region was quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO. (D) Western blot analysis of TGF-β1 protein levels. TGF-β1 protein levels in each treatment group (n = 3 per group) were quantified. A-D are representative of at least three similar experiments. Scale bar: 100μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
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f5: P311 deficiency suppresses TGF-β1 expression in UUO mice.(A) RNA was isolated in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. TGF-β1 mRNA expression was determined by real-time PCR. (B) Representative photomicrographs of TGF-β1-specific immunohistochemical staining of UUO kidneys from P311+/+ and P311−/−mice on day 7. Black arrowhead indicates the TGF-β1-positive region. Bottom panel: negative controls for the immunohistochemical staining of TGF-β1 on the obstructed kidneys from both P311+/+ and P311−/− mice. (C) TGF-β1-positive region was quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO. (D) Western blot analysis of TGF-β1 protein levels. TGF-β1 protein levels in each treatment group (n = 3 per group) were quantified. A-D are representative of at least three similar experiments. Scale bar: 100μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.

Mentions: α-SMA is a key marker of myofibroblasts, which are be the interstitial cells that are responsible for fibrosis25. Therefore, we examined whether P311 induced α-SMA expression. We assessed α-SMA mRNA and protein levels in both P311+/+ and P311−/− kidneys after UUO or sham operation. As shown in Fig. 5A, α-SMA mRNA expression was low in both the P311+/+ and P311−/− Sham groups, but was induced by UUO. However, α-SMA mRNA expression was higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 4A, 1.93-fold difference, P < 0.001). Immunohistochemical analyses revealed that α-SMA protein localized to the cytoplasm of some tubular epithelial cells and interstitial cells in obstructed kidneys from both P311+/+ and P311−/− mice (Fig. 4B). However, the intensity of α-SMA expression, as determined by morphometric quantification, was significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 4C, 3.05-fold difference, P = 0.014). Consistent with these observations, western blot analysis showed that α-SMA protein expression was significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 4D, 1.48-fold difference, P = 0.032). No α-SMA expression was detected in the Sham groups (Fig. 4D). These data implied that P311 is involved in EMT in renal fibrogenesis.


P311 promotes renal fibrosis via TGFβ1/Smad signaling.

Yao Z, Yang S, He W, Li L, Xu R, Zhang X, Li H, Zhan R, Sun W, Tan J, Zhou J, Luo G, Wu J - Sci Rep (2015)

P311 deficiency suppresses TGF-β1 expression in UUO mice.(A) RNA was isolated in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. TGF-β1 mRNA expression was determined by real-time PCR. (B) Representative photomicrographs of TGF-β1-specific immunohistochemical staining of UUO kidneys from P311+/+ and P311−/−mice on day 7. Black arrowhead indicates the TGF-β1-positive region. Bottom panel: negative controls for the immunohistochemical staining of TGF-β1 on the obstructed kidneys from both P311+/+ and P311−/− mice. (C) TGF-β1-positive region was quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO. (D) Western blot analysis of TGF-β1 protein levels. TGF-β1 protein levels in each treatment group (n = 3 per group) were quantified. A-D are representative of at least three similar experiments. Scale bar: 100μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
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Related In: Results  -  Collection

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f5: P311 deficiency suppresses TGF-β1 expression in UUO mice.(A) RNA was isolated in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. TGF-β1 mRNA expression was determined by real-time PCR. (B) Representative photomicrographs of TGF-β1-specific immunohistochemical staining of UUO kidneys from P311+/+ and P311−/−mice on day 7. Black arrowhead indicates the TGF-β1-positive region. Bottom panel: negative controls for the immunohistochemical staining of TGF-β1 on the obstructed kidneys from both P311+/+ and P311−/− mice. (C) TGF-β1-positive region was quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO. (D) Western blot analysis of TGF-β1 protein levels. TGF-β1 protein levels in each treatment group (n = 3 per group) were quantified. A-D are representative of at least three similar experiments. Scale bar: 100μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
Mentions: α-SMA is a key marker of myofibroblasts, which are be the interstitial cells that are responsible for fibrosis25. Therefore, we examined whether P311 induced α-SMA expression. We assessed α-SMA mRNA and protein levels in both P311+/+ and P311−/− kidneys after UUO or sham operation. As shown in Fig. 5A, α-SMA mRNA expression was low in both the P311+/+ and P311−/− Sham groups, but was induced by UUO. However, α-SMA mRNA expression was higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 4A, 1.93-fold difference, P < 0.001). Immunohistochemical analyses revealed that α-SMA protein localized to the cytoplasm of some tubular epithelial cells and interstitial cells in obstructed kidneys from both P311+/+ and P311−/− mice (Fig. 4B). However, the intensity of α-SMA expression, as determined by morphometric quantification, was significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 4C, 3.05-fold difference, P = 0.014). Consistent with these observations, western blot analysis showed that α-SMA protein expression was significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 4D, 1.48-fold difference, P = 0.032). No α-SMA expression was detected in the Sham groups (Fig. 4D). These data implied that P311 is involved in EMT in renal fibrogenesis.

Bottom Line: We previously observed that P311 is highly expressed in skin hypertrophic scars.The interstitial deposition of collagen, α-SMA and TGF-β1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out.In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.

ABSTRACT
P311, a gene that was identified in 1993, has been found to have diverse biological functions in processes such as cell proliferation, migration and differentiation. However, its role in fibrosis is unknown. We previously observed that P311 is highly expressed in skin hypertrophic scars. In this study, P311 over-expression was detected in a subset of tubular epithelial cells in clinical biopsy specimens of renal fibrosis; this over-expression, was found concurrent with α-smooth muscle actin (α-SMA) and transforming growth factor beta1 (TGFβ1) expression. Subsequently, these results were verified in a mouse experimental renal fibrosis model induced by unilateral ureteral obstruction. The interstitial deposition of collagen, α-SMA and TGF-β1 expression, and macrophage infiltration were dramatically decreased when P311 was knocked out. Moreover, TGFβ/Smad signaling had a critical effect on the promotion of renal fibrosis by P311. In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis.

No MeSH data available.


Related in: MedlinePlus