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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 and unilateral ureteral obstruction (UUO) had similar inhibitory effects on Pin 1 activity. Pin 1 activity was measured in whole kidney protein lysates after 2 weeks of UUO as previously described [18]. Mean values and standard error bars from UUO and control kidneys are represented for each time point.
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Figure 2: Juglone and unilateral ureteral obstruction (UUO) had similar inhibitory effects on Pin 1 activity. Pin 1 activity was measured in whole kidney protein lysates after 2 weeks of UUO as previously described [18]. Mean values and standard error bars from UUO and control kidneys are represented for each time point.

Mentions: We next examined Pin 1 activity in unobstructed and obstructed kidneys in control or juglone-treated rats. These analyses would help us determine whether the antifibrotic properties of juglone resulted from Pin 1 blockade. The studies demonstrated that juglone effectively inhibited Pin 1 activity in unobstructed right kidneys (Figure 2). However, Pin 1 activity was significantly decreased in left obstructed kidneys regardless of treatment status (Figure 2). Pin 1 activity in obstructed kidneys was reduced to the same level as in unobstructed kidneys treated with juglone. In aggregate, these studies suggest that the antifibrotic effects of juglone are independent from Pin 1 blockade during UUO.


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 and unilateral ureteral obstruction (UUO) had similar inhibitory effects on Pin 1 activity. Pin 1 activity was measured in whole kidney protein lysates after 2 weeks of UUO as previously described [18]. Mean values and standard error bars from UUO and control kidneys are represented for each time point.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Juglone and unilateral ureteral obstruction (UUO) had similar inhibitory effects on Pin 1 activity. Pin 1 activity was measured in whole kidney protein lysates after 2 weeks of UUO as previously described [18]. Mean values and standard error bars from UUO and control kidneys are represented for each time point.
Mentions: We next examined Pin 1 activity in unobstructed and obstructed kidneys in control or juglone-treated rats. These analyses would help us determine whether the antifibrotic properties of juglone resulted from Pin 1 blockade. The studies demonstrated that juglone effectively inhibited Pin 1 activity in unobstructed right kidneys (Figure 2). However, Pin 1 activity was significantly decreased in left obstructed kidneys regardless of treatment status (Figure 2). Pin 1 activity in obstructed kidneys was reduced to the same level as in unobstructed kidneys treated with juglone. In aggregate, these studies suggest that the antifibrotic effects of juglone are independent from Pin 1 blockade during UUO.

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