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The Pin 1 inhibitor juglone attenuates kidney fibrogenesis via Pin 1-independent mechanisms in the unilateral ureteral occlusion model.

Reese S, Vidyasagar A, Jacobson L, Acun Z, Esnault S, Hullett D, Malter JS, Djamali A - Fibrogenesis Tissue Repair (2010)

Bottom Line: Juglone also reduced EMT (alpha-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney.In vitro, juglone (1 muM) significantly decreased alpha-SMA and p-smad levels compared to vehicle.The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Medicine and Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA. axd@medicine.wisc.edu.

ABSTRACT

Background: Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E).

Results: After 2 weeks of UUO, immunoblot analyses demonstrated that juglone (0.25 and 1 mg/kg/24 h) inhibited the deposition of matrix (alpha-smooth muscle actin (SMA), collagen type III and vimentin) and the activation of signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27). Juglone also reduced EMT (alpha-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney. There was no difference in Pin 1 levels between treatment and control groups. Pin 1 activity was significantly decreased in obstructed kidneys regardless of treatment status. In vitro, juglone (1 muM) significantly decreased alpha-SMA and p-smad levels compared to vehicle.

Conclusions: Juglone attenuates fibrogenesis via Pin 1-independent mechanisms in the UUO model. The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress.

No MeSH data available.


Related in: MedlinePlus

Juglone reduced fibrogenesis after unilateral ureteral obstruction (UUO). Male Lewis rats (3 months old) underwent UUO of the left kidney for 2 weeks. There were three groups receiving vehicle or juglone (0.25 mg/kg/day or 1 mg/kg/day) for 2 weeks starting the day of surgery. (a) Immunoblot analyses of left kidney from control or juglone-treated rats for the proteins shown along the left. (b) Multiple (n = 3) immunoblots were quantitated and signals expressed as arbitrary units after normalization to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) signal.
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Figure 1: Juglone reduced fibrogenesis after unilateral ureteral obstruction (UUO). Male Lewis rats (3 months old) underwent UUO of the left kidney for 2 weeks. There were three groups receiving vehicle or juglone (0.25 mg/kg/day or 1 mg/kg/day) for 2 weeks starting the day of surgery. (a) Immunoblot analyses of left kidney from control or juglone-treated rats for the proteins shown along the left. (b) Multiple (n = 3) immunoblots were quantitated and signals expressed as arbitrary units after normalization to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) signal.

Mentions: Male Lewis rats (3 months old) underwent UUO of the left kidney for 2 weeks. There were three groups receiving vehicle, juglone 0.25 mg/kg/day or juglone 1 mg/kg/day for 2 weeks starting the day of surgery. There was no animal death associated with treatment. Treated animals had a 10% weight loss in the first week after surgery, which resolved by the end of week 2. Immunoblot analyses for Pin 1, biomarkers of matrix remodeling (α-smooth muscle actin (SMA), collagen type III and vimentin) and signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27) demonstrated that juglone therapy decreased α-SMA, collagen type III, vimentin, p-smad2 and p-HSP27 levels (Figure 1). There was no difference in Pin 1 levels between treatment and control groups suggesting that juglone inhibits fibrogenesis independently of Pin 1 levels in the UUO model.


The Pin 1 inhibitor juglone attenuates kidney fibrogenesis via Pin 1-independent mechanisms in the unilateral ureteral occlusion model.

Reese S, Vidyasagar A, Jacobson L, Acun Z, Esnault S, Hullett D, Malter JS, Djamali A - Fibrogenesis Tissue Repair (2010)

Juglone reduced fibrogenesis after unilateral ureteral obstruction (UUO). Male Lewis rats (3 months old) underwent UUO of the left kidney for 2 weeks. There were three groups receiving vehicle or juglone (0.25 mg/kg/day or 1 mg/kg/day) for 2 weeks starting the day of surgery. (a) Immunoblot analyses of left kidney from control or juglone-treated rats for the proteins shown along the left. (b) Multiple (n = 3) immunoblots were quantitated and signals expressed as arbitrary units after normalization to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) signal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2823698&req=5

Figure 1: Juglone reduced fibrogenesis after unilateral ureteral obstruction (UUO). Male Lewis rats (3 months old) underwent UUO of the left kidney for 2 weeks. There were three groups receiving vehicle or juglone (0.25 mg/kg/day or 1 mg/kg/day) for 2 weeks starting the day of surgery. (a) Immunoblot analyses of left kidney from control or juglone-treated rats for the proteins shown along the left. (b) Multiple (n = 3) immunoblots were quantitated and signals expressed as arbitrary units after normalization to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) signal.
Mentions: Male Lewis rats (3 months old) underwent UUO of the left kidney for 2 weeks. There were three groups receiving vehicle, juglone 0.25 mg/kg/day or juglone 1 mg/kg/day for 2 weeks starting the day of surgery. There was no animal death associated with treatment. Treated animals had a 10% weight loss in the first week after surgery, which resolved by the end of week 2. Immunoblot analyses for Pin 1, biomarkers of matrix remodeling (α-smooth muscle actin (SMA), collagen type III and vimentin) and signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27) demonstrated that juglone therapy decreased α-SMA, collagen type III, vimentin, p-smad2 and p-HSP27 levels (Figure 1). There was no difference in Pin 1 levels between treatment and control groups suggesting that juglone inhibits fibrogenesis independently of Pin 1 levels in the UUO model.

Bottom Line: Juglone also reduced EMT (alpha-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney.In vitro, juglone (1 muM) significantly decreased alpha-SMA and p-smad levels compared to vehicle.The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Medicine and Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA. axd@medicine.wisc.edu.

ABSTRACT

Background: Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E).

Results: After 2 weeks of UUO, immunoblot analyses demonstrated that juglone (0.25 and 1 mg/kg/24 h) inhibited the deposition of matrix (alpha-smooth muscle actin (SMA), collagen type III and vimentin) and the activation of signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27). Juglone also reduced EMT (alpha-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney. There was no difference in Pin 1 levels between treatment and control groups. Pin 1 activity was significantly decreased in obstructed kidneys regardless of treatment status. In vitro, juglone (1 muM) significantly decreased alpha-SMA and p-smad levels compared to vehicle.

Conclusions: Juglone attenuates fibrogenesis via Pin 1-independent mechanisms in the UUO model. The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress.

No MeSH data available.


Related in: MedlinePlus