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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 renal fibrosis in UUO mice.(A) Histologic changes in the cortex and medulla of kidneys from P311+/+ and P311−/− mice. Representative hematoxylin and eosin staining of renal cortex and medulla sections from the Sham and UUO groups of both P311+/+ (left) (n = 6) and P311−/− (right) (n = 6) mice on day 7. Black arrowhead indicates the remarkable tubular atrophy. (B) Representative photomicrographs of Masson’s trichrome staining of kidney sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. Black arrowhead indicates the interstitial collagen fibril deposition. (C) Fibrotic areas were quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. (D) RNA was isolated from kidneys of P311+/+ (n = 6) and P311−/− (n = 6) mice after UUO or sham operation. Collagen I mRNA expression was determined by real-time PCR. (E) Western blot analysis of vimentin protein levels. (F) Quantification of vimentin protein levels in each treatment group (n = 3 per group). A-F are representative of at least three similar experiments. Scale bar: 100 μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
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f3: P311 deficiency suppresses renal fibrosis in UUO mice.(A) Histologic changes in the cortex and medulla of kidneys from P311+/+ and P311−/− mice. Representative hematoxylin and eosin staining of renal cortex and medulla sections from the Sham and UUO groups of both P311+/+ (left) (n = 6) and P311−/− (right) (n = 6) mice on day 7. Black arrowhead indicates the remarkable tubular atrophy. (B) Representative photomicrographs of Masson’s trichrome staining of kidney sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. Black arrowhead indicates the interstitial collagen fibril deposition. (C) Fibrotic areas were quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. (D) RNA was isolated from kidneys of P311+/+ (n = 6) and P311−/− (n = 6) mice after UUO or sham operation. Collagen I mRNA expression was determined by real-time PCR. (E) Western blot analysis of vimentin protein levels. (F) Quantification of vimentin protein levels in each treatment group (n = 3 per group). A-F are representative of at least three similar experiments. Scale bar: 100 μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.

Mentions: The above findings suggested a potential functional role for P311 in renal fibrosis. To examine this hypothesis, we analyzed P311−/− mice and found that obstructed kidneys in both P311+/+ and P311−/− mice exhibited tubular dilation and atrophy, interstitial matrix deposition and inflammatory cell infiltration (Fig. 3A). These changes were more severe in P311+/+ mice. Quantitative analysis of Masson trichrome-positive areas revealed an approximately 1.43-fold increase in interstitial collagen deposition in P311+/+ mice compared to P311−/− mice after UUO (Fig. 3B,C, P = 0.005). Real-time PCR showed that collagen I mRNA levels were very low in the P311+/+ and P311−/− Sham groups, but were significantly increased in the UUO groups. However, collagen I mRNA expression increased more in P311+/+ mice than in P311−/− mice after UUO (Fig. 3D, 1.69-fold difference, P = 0.010). Vimentin expression was significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice, as determined by western blot (Fig. 3E,F, 1.52-fold difference, P = 0.024). Therefore, these results suggested that P311 promotes renal fibrogenesis in a mouse model of UUO.


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 renal fibrosis in UUO mice.(A) Histologic changes in the cortex and medulla of kidneys from P311+/+ and P311−/− mice. Representative hematoxylin and eosin staining of renal cortex and medulla sections from the Sham and UUO groups of both P311+/+ (left) (n = 6) and P311−/− (right) (n = 6) mice on day 7. Black arrowhead indicates the remarkable tubular atrophy. (B) Representative photomicrographs of Masson’s trichrome staining of kidney sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. Black arrowhead indicates the interstitial collagen fibril deposition. (C) Fibrotic areas were quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. (D) RNA was isolated from kidneys of P311+/+ (n = 6) and P311−/− (n = 6) mice after UUO or sham operation. Collagen I mRNA expression was determined by real-time PCR. (E) Western blot analysis of vimentin protein levels. (F) Quantification of vimentin protein levels in each treatment group (n = 3 per group). A-F are representative of at least three similar experiments. Scale bar: 100 μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f3: P311 deficiency suppresses renal fibrosis in UUO mice.(A) Histologic changes in the cortex and medulla of kidneys from P311+/+ and P311−/− mice. Representative hematoxylin and eosin staining of renal cortex and medulla sections from the Sham and UUO groups of both P311+/+ (left) (n = 6) and P311−/− (right) (n = 6) mice on day 7. Black arrowhead indicates the remarkable tubular atrophy. (B) Representative photomicrographs of Masson’s trichrome staining of kidney sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. Black arrowhead indicates the interstitial collagen fibril deposition. (C) Fibrotic areas were quantified in stained sections from P311+/+ (n = 6) and P311−/− (n = 6) mice at day 7 after UUO. (D) RNA was isolated from kidneys of P311+/+ (n = 6) and P311−/− (n = 6) mice after UUO or sham operation. Collagen I mRNA expression was determined by real-time PCR. (E) Western blot analysis of vimentin protein levels. (F) Quantification of vimentin protein levels in each treatment group (n = 3 per group). A-F are representative of at least three similar experiments. Scale bar: 100 μm. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
Mentions: The above findings suggested a potential functional role for P311 in renal fibrosis. To examine this hypothesis, we analyzed P311−/− mice and found that obstructed kidneys in both P311+/+ and P311−/− mice exhibited tubular dilation and atrophy, interstitial matrix deposition and inflammatory cell infiltration (Fig. 3A). These changes were more severe in P311+/+ mice. Quantitative analysis of Masson trichrome-positive areas revealed an approximately 1.43-fold increase in interstitial collagen deposition in P311+/+ mice compared to P311−/− mice after UUO (Fig. 3B,C, P = 0.005). Real-time PCR showed that collagen I mRNA levels were very low in the P311+/+ and P311−/− Sham groups, but were significantly increased in the UUO groups. However, collagen I mRNA expression increased more in P311+/+ mice than in P311−/− mice after UUO (Fig. 3D, 1.69-fold difference, P = 0.010). Vimentin expression was significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice, as determined by western blot (Fig. 3E,F, 1.52-fold difference, P = 0.024). Therefore, these results suggested that P311 promotes renal fibrogenesis in a mouse model of UUO.

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