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Smad7 protects against chronic aristolochic acid nephropathy in mice.

Dai XY, Zhou L, Huang XR, Fu P, Lan HY - Oncotarget (2015)

Bottom Line: However, treatment for chronic AAN remains ineffective.Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation.In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.

ABSTRACT
Chronic Aristolochic Acid Nephropathy (AAN) is a progressive chronic kidney disease related to herb medicine. However, treatment for chronic AAN remains ineffective. We report here that Smad7 is protective and has therapeutic potential for chronic AAN. In a mouse model of chronic AAN, progressive renal injury was associated with a loss of renal Smad7 and disruption of Smad7 largely aggravated the severity of chronic AAN as demonstrated by a significant increase in levels of 24-hour urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. In contrast, restored Smad7 locally in the kidneys of Smad7 knockout mice prevented the progression of chronic AAN. Further studies revealed that worsen chronic AAN in Smad7 knockout mice was associated with enhanced activation of TGF-β/Smad3 and NF-κB signaling pathways, which was reversed when renal Smad7 was restored. Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation. In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN.

No MeSH data available.


Related in: MedlinePlus

Disruption of Smad7 enhances AA-induced renal fibrosis and inflammation at day 42 after induction of AANA and B: Renal collagen I and α-SMA mRNA and protein expression by real-time PCR and western blot analysis. C and D: Renal infiltration of F4/80+macrophages and CD3+ T cells detected by immunohistochemistry. E and F: MCP-1 and TNFα mRNA expression detected by real-time PCR. Results show that compared with the WT mice, Smad7 KO mice show a significant increase in renal fibrosis and inflammation. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN mice. Magnification: x400.
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Figure 2: Disruption of Smad7 enhances AA-induced renal fibrosis and inflammation at day 42 after induction of AANA and B: Renal collagen I and α-SMA mRNA and protein expression by real-time PCR and western blot analysis. C and D: Renal infiltration of F4/80+macrophages and CD3+ T cells detected by immunohistochemistry. E and F: MCP-1 and TNFα mRNA expression detected by real-time PCR. Results show that compared with the WT mice, Smad7 KO mice show a significant increase in renal fibrosis and inflammation. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN mice. Magnification: x400.

Mentions: Compared with normal mice, after intraperitoneal injection of AA for 6 weeks, Smad7 WT mice developed chronic AAN as evidenced by severe tubulointerstitial fibrosis accompanied by dilated tubular lumens with bared tubular basement membrane and an increase in 24h proteinuria and serum creatinine (Fig. 1). All these changes were further acerbated in Smad7 KO mice with chronic AAN (Fig. 1). Analysis with immunohistochemistry, western blot, and real-time PCR also revealed that compared to WT mice, deletion of Smad7 largely enhanced expression of collagen I and α-SMA and promoted renal inflammation including expression of tumor necrosis factor-α (TNFα), chemokine monocyte chemoattractant protein-1 (MCP-1), and a marked infiltration of F4/80+ macrophages and CD3+ T cells (Fig. 2 and Fig. S1 and S2).


Smad7 protects against chronic aristolochic acid nephropathy in mice.

Dai XY, Zhou L, Huang XR, Fu P, Lan HY - Oncotarget (2015)

Disruption of Smad7 enhances AA-induced renal fibrosis and inflammation at day 42 after induction of AANA and B: Renal collagen I and α-SMA mRNA and protein expression by real-time PCR and western blot analysis. C and D: Renal infiltration of F4/80+macrophages and CD3+ T cells detected by immunohistochemistry. E and F: MCP-1 and TNFα mRNA expression detected by real-time PCR. Results show that compared with the WT mice, Smad7 KO mice show a significant increase in renal fibrosis and inflammation. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN mice. Magnification: x400.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4494914&req=5

Figure 2: Disruption of Smad7 enhances AA-induced renal fibrosis and inflammation at day 42 after induction of AANA and B: Renal collagen I and α-SMA mRNA and protein expression by real-time PCR and western blot analysis. C and D: Renal infiltration of F4/80+macrophages and CD3+ T cells detected by immunohistochemistry. E and F: MCP-1 and TNFα mRNA expression detected by real-time PCR. Results show that compared with the WT mice, Smad7 KO mice show a significant increase in renal fibrosis and inflammation. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN mice. Magnification: x400.
Mentions: Compared with normal mice, after intraperitoneal injection of AA for 6 weeks, Smad7 WT mice developed chronic AAN as evidenced by severe tubulointerstitial fibrosis accompanied by dilated tubular lumens with bared tubular basement membrane and an increase in 24h proteinuria and serum creatinine (Fig. 1). All these changes were further acerbated in Smad7 KO mice with chronic AAN (Fig. 1). Analysis with immunohistochemistry, western blot, and real-time PCR also revealed that compared to WT mice, deletion of Smad7 largely enhanced expression of collagen I and α-SMA and promoted renal inflammation including expression of tumor necrosis factor-α (TNFα), chemokine monocyte chemoattractant protein-1 (MCP-1), and a marked infiltration of F4/80+ macrophages and CD3+ T cells (Fig. 2 and Fig. S1 and S2).

Bottom Line: However, treatment for chronic AAN remains ineffective.Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation.In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.

ABSTRACT
Chronic Aristolochic Acid Nephropathy (AAN) is a progressive chronic kidney disease related to herb medicine. However, treatment for chronic AAN remains ineffective. We report here that Smad7 is protective and has therapeutic potential for chronic AAN. In a mouse model of chronic AAN, progressive renal injury was associated with a loss of renal Smad7 and disruption of Smad7 largely aggravated the severity of chronic AAN as demonstrated by a significant increase in levels of 24-hour urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. In contrast, restored Smad7 locally in the kidneys of Smad7 knockout mice prevented the progression of chronic AAN. Further studies revealed that worsen chronic AAN in Smad7 knockout mice was associated with enhanced activation of TGF-β/Smad3 and NF-κB signaling pathways, which was reversed when renal Smad7 was restored. Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation. In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN.

No MeSH data available.


Related in: MedlinePlus