Limits...
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 down-regulates TGF-β/Smad signaling in UUO mice.(A) TβR I mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) after mice 7 days after UUO or sham operation. (B) TβR II mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. (C) p-Smad2, p-Smad3, Smad2, Smad3, Smad4, Smad7 and GAPDH protein levels were determined in kidneys by western blot. (D) Relative density of Smad2 protein (n = 3 per group) in each treatment group. (E) Relative density of Smad3 protein (n = 3 per group) in each treatment group. (F) Relative density of p-Smad2 protein (n = 3 per group) in each treatment group. (G) Relative density of p-Smad3 protein (n = 3 per group) in each treatment group. (H) Relative density of Smad4 protein (n = 3 per group) in each treatment group. (I) Relative density of Smad7 protein (n = 3 per group) in each treatment group. A-I are representative of at least three similar experiments. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4663757&req=5

f6: P311 deficiency down-regulates TGF-β/Smad signaling in UUO mice.(A) TβR I mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) after mice 7 days after UUO or sham operation. (B) TβR II mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. (C) p-Smad2, p-Smad3, Smad2, Smad3, Smad4, Smad7 and GAPDH protein levels were determined in kidneys by western blot. (D) Relative density of Smad2 protein (n = 3 per group) in each treatment group. (E) Relative density of Smad3 protein (n = 3 per group) in each treatment group. (F) Relative density of p-Smad2 protein (n = 3 per group) in each treatment group. (G) Relative density of p-Smad3 protein (n = 3 per group) in each treatment group. (H) Relative density of Smad4 protein (n = 3 per group) in each treatment group. (I) Relative density of Smad7 protein (n = 3 per group) in each treatment group. A-I are representative of at least three similar experiments. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.

Mentions: We further examined the type I TGF-β receptor (TβR I), type II TGF-β receptor (TβR II) and downstream targets of Smad signaling. We found that TβR I and TβR II mRNA levels were dramatically increased in both the P311+/+ and P311−/− UUO groups compared to the Sham groups but were higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 6A, TβR I, P311+/+ compared to P311−/−, 2.25-fold difference, P = 0.001; Fig. 6B, TβR II, P311+/+ compared to P311−/−, 1.71-fold difference, P < 0.001). Total Smad2 and Smad3 protein levels were markedly increased in obstructed kidneys from both P311+/+ and P311−/− mice, but were significantly higher in the former than in the latter (Fig. 6C,D, Smad2, P311+/+ compared to P311−/−, 1.65-fold difference, P = 0.007; Fig. 6C,E, Smad3, P311+/+ compared to P311−/−, 4.03-fold difference, P < 0.001). Moreover, phosphorylated Smad2 (p-Smad2) and phosphorylated Smad3 (p-Smad3) levels were significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 6C,F, p-Smad2, P311+/+ compared to P311−/−, 1.80-fold difference, P = 0.002; Fig. 6C,G, p-Smad3, P311+/+ compared to P311−/−, 2.01-fold difference, P = 0.001). Smad4 expression was also increased in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 6C,H, 2.16-fold difference, P < 0.001). After UUO, Smad7 protein levels in both P311+/+ and P311−/− kidneys decreased compared to the sham operation. Unexpectedly, Smad7 levels were higher in P311+/+ kidneys than in P311−/− kidneys after UUO (Fig. 6C,I, 2.50-fold difference, P = 0.008). Taken together, these data showed that P311 deficiency down-regulated TGF-β1 expression, TGF-β1 receptors expression and TGF-β1/Smad signaling activation.


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 down-regulates TGF-β/Smad signaling in UUO mice.(A) TβR I mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) after mice 7 days after UUO or sham operation. (B) TβR II mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. (C) p-Smad2, p-Smad3, Smad2, Smad3, Smad4, Smad7 and GAPDH protein levels were determined in kidneys by western blot. (D) Relative density of Smad2 protein (n = 3 per group) in each treatment group. (E) Relative density of Smad3 protein (n = 3 per group) in each treatment group. (F) Relative density of p-Smad2 protein (n = 3 per group) in each treatment group. (G) Relative density of p-Smad3 protein (n = 3 per group) in each treatment group. (H) Relative density of Smad4 protein (n = 3 per group) in each treatment group. (I) Relative density of Smad7 protein (n = 3 per group) in each treatment group. A-I are representative of at least three similar experiments. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663757&req=5

f6: P311 deficiency down-regulates TGF-β/Smad signaling in UUO mice.(A) TβR I mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) after mice 7 days after UUO or sham operation. (B) TβR II mRNA expression was determined by real-time PCR in kidneys from P311+/+ (n = 6) and P311−/− (n = 6) mice 7 days after UUO or sham operation. (C) p-Smad2, p-Smad3, Smad2, Smad3, Smad4, Smad7 and GAPDH protein levels were determined in kidneys by western blot. (D) Relative density of Smad2 protein (n = 3 per group) in each treatment group. (E) Relative density of Smad3 protein (n = 3 per group) in each treatment group. (F) Relative density of p-Smad2 protein (n = 3 per group) in each treatment group. (G) Relative density of p-Smad3 protein (n = 3 per group) in each treatment group. (H) Relative density of Smad4 protein (n = 3 per group) in each treatment group. (I) Relative density of Smad7 protein (n = 3 per group) in each treatment group. A-I are representative of at least three similar experiments. Data are presented as the mean ± SD. *P < 0.05; **P < 0.01.
Mentions: We further examined the type I TGF-β receptor (TβR I), type II TGF-β receptor (TβR II) and downstream targets of Smad signaling. We found that TβR I and TβR II mRNA levels were dramatically increased in both the P311+/+ and P311−/− UUO groups compared to the Sham groups but were higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 6A, TβR I, P311+/+ compared to P311−/−, 2.25-fold difference, P = 0.001; Fig. 6B, TβR II, P311+/+ compared to P311−/−, 1.71-fold difference, P < 0.001). Total Smad2 and Smad3 protein levels were markedly increased in obstructed kidneys from both P311+/+ and P311−/− mice, but were significantly higher in the former than in the latter (Fig. 6C,D, Smad2, P311+/+ compared to P311−/−, 1.65-fold difference, P = 0.007; Fig. 6C,E, Smad3, P311+/+ compared to P311−/−, 4.03-fold difference, P < 0.001). Moreover, phosphorylated Smad2 (p-Smad2) and phosphorylated Smad3 (p-Smad3) levels were significantly higher in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 6C,F, p-Smad2, P311+/+ compared to P311−/−, 1.80-fold difference, P = 0.002; Fig. 6C,G, p-Smad3, P311+/+ compared to P311−/−, 2.01-fold difference, P = 0.001). Smad4 expression was also increased in obstructed kidneys from P311+/+ mice compared to P311−/− mice (Fig. 6C,H, 2.16-fold difference, P < 0.001). After UUO, Smad7 protein levels in both P311+/+ and P311−/− kidneys decreased compared to the sham operation. Unexpectedly, Smad7 levels were higher in P311+/+ kidneys than in P311−/− kidneys after UUO (Fig. 6C,I, 2.50-fold difference, P = 0.008). Taken together, these data showed that P311 deficiency down-regulated TGF-β1 expression, TGF-β1 receptors expression and TGF-β1/Smad signaling activation.

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