Limits...
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

The effects of juglone on fibrogenesis may be mediated by smad2. Proximal tubular cells were untreated, treated with vehicle, or juglone as shown for 48 h prior to lysis and (a) western blotting for the proteins shown along the left. In (b), three independent experiments were quantitated after normalization to actin signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2823698&req=5

Figure 5: The effects of juglone on fibrogenesis may be mediated by smad2. Proximal tubular cells were untreated, treated with vehicle, or juglone as shown for 48 h prior to lysis and (a) western blotting for the proteins shown along the left. In (b), three independent experiments were quantitated after normalization to actin signals.

Mentions: To determine whether juglone inhibited TGFβ 1 activity we evaluated phospho-smad2 activity in normal kidneys compared to obstructed kidneys treated or not with juglone (Figure 4). These studies demonstrated that nuclear p-smad2 was significantly increased after UUO and that juglone prevented nuclear p-smad2 activity. Lastly, we evaluated the effects of juglone on α-SMA and activated smad2 (p-smad2) levels in proximal tubular epithelial cells. Juglone (1 μM) significantly reduced α-SMA and p-smad2 levels, consistent with our in vivo studies and suggesting that juglone may inhibit smad2 phosphorylation and activation in tubular epithelial cells (Figure 5).


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)

The effects of juglone on fibrogenesis may be mediated by smad2. Proximal tubular cells were untreated, treated with vehicle, or juglone as shown for 48 h prior to lysis and (a) western blotting for the proteins shown along the left. In (b), three independent experiments were quantitated after normalization to actin signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: The effects of juglone on fibrogenesis may be mediated by smad2. Proximal tubular cells were untreated, treated with vehicle, or juglone as shown for 48 h prior to lysis and (a) western blotting for the proteins shown along the left. In (b), three independent experiments were quantitated after normalization to actin signals.
Mentions: To determine whether juglone inhibited TGFβ 1 activity we evaluated phospho-smad2 activity in normal kidneys compared to obstructed kidneys treated or not with juglone (Figure 4). These studies demonstrated that nuclear p-smad2 was significantly increased after UUO and that juglone prevented nuclear p-smad2 activity. Lastly, we evaluated the effects of juglone on α-SMA and activated smad2 (p-smad2) levels in proximal tubular epithelial cells. Juglone (1 μM) significantly reduced α-SMA and p-smad2 levels, consistent with our in vivo studies and suggesting that juglone may inhibit smad2 phosphorylation and activation in tubular epithelial cells (Figure 5).

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