Limits...
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

Local Smad7 therapy inhibits progressive renal fibrosis and inflammation in Smad7 WT mice with established chronic AAN at day 42A 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 to Smad7 WT mice with chronic AAN without treatment (AAN-UT) or treated with vector control (AAN-VC), Smad7 treatment (AAN-Smad7) locally in the kidney with the established AAN from day 14 to day 42 blocks renal fibrosis and inflammation at day 42. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P<0.001 compared with saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN treated with or without VC. †P < 0.05, ††P < 0.01, †††P < 0.001 compared with AAN at day 14 before Smad7 treatment. Magnification: x400.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494914&req=5

Figure 8: Local Smad7 therapy inhibits progressive renal fibrosis and inflammation in Smad7 WT mice with established chronic AAN at day 42A 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 to Smad7 WT mice with chronic AAN without treatment (AAN-UT) or treated with vector control (AAN-VC), Smad7 treatment (AAN-Smad7) locally in the kidney with the established AAN from day 14 to day 42 blocks renal fibrosis and inflammation at day 42. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P<0.001 compared with saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN treated with or without VC. †P < 0.05, ††P < 0.01, †††P < 0.001 compared with AAN at day 14 before Smad7 treatment. Magnification: x400.

Mentions: To explore whether Smad7 has therapeutic effect on chronic AAN, we transferred Smad7 gene into the diseased kidney of Smad7 WT mice with established chronic AAN at day 14 after AA administration. Results showed that compared with control-treated AAN mice at day 42, AAN mice received Smad7 treatment from day 14 to day 42 after induction of AAN were protected from progressive renal histological and functional injury (Fig. 7). Further studies also detected that Smad7 treatment largely inhibited a marked upregulation of collagen I and α-SMA and suppressed renal inflammation including expression of MCP-1 and TNFα, and infiltration of macrophages and T cells within the diseased kidney (Fig. 8 and Figs. S7 and S8).


Smad7 protects against chronic aristolochic acid nephropathy in mice.

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

Local Smad7 therapy inhibits progressive renal fibrosis and inflammation in Smad7 WT mice with established chronic AAN at day 42A 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 to Smad7 WT mice with chronic AAN without treatment (AAN-UT) or treated with vector control (AAN-VC), Smad7 treatment (AAN-Smad7) locally in the kidney with the established AAN from day 14 to day 42 blocks renal fibrosis and inflammation at day 42. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P<0.001 compared with saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN treated with or without VC. †P < 0.05, ††P < 0.01, †††P < 0.001 compared with AAN at day 14 before Smad7 treatment. Magnification: x400.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Local Smad7 therapy inhibits progressive renal fibrosis and inflammation in Smad7 WT mice with established chronic AAN at day 42A 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 to Smad7 WT mice with chronic AAN without treatment (AAN-UT) or treated with vector control (AAN-VC), Smad7 treatment (AAN-Smad7) locally in the kidney with the established AAN from day 14 to day 42 blocks renal fibrosis and inflammation at day 42. Data are expressed as mean ± SE for groups of 6 mice. *P < 0.05, **P < 0.01, ***P<0.001 compared with saline control mice. #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Smad7 WT mice with chronic AAN treated with or without VC. †P < 0.05, ††P < 0.01, †††P < 0.001 compared with AAN at day 14 before Smad7 treatment. Magnification: x400.
Mentions: To explore whether Smad7 has therapeutic effect on chronic AAN, we transferred Smad7 gene into the diseased kidney of Smad7 WT mice with established chronic AAN at day 14 after AA administration. Results showed that compared with control-treated AAN mice at day 42, AAN mice received Smad7 treatment from day 14 to day 42 after induction of AAN were protected from progressive renal histological and functional injury (Fig. 7). Further studies also detected that Smad7 treatment largely inhibited a marked upregulation of collagen I and α-SMA and suppressed renal inflammation including expression of MCP-1 and TNFα, and infiltration of macrophages and T cells within the diseased kidney (Fig. 8 and Figs. S7 and S8).

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