Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants

Pat, Betty, Yang, Tao, Kong, Chuize, Watters, Dianne, Johnson, David W. and Gobe, Glenda (2005) Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants. Kidney International, 67 3: 931-943.


Author Pat, Betty
Yang, Tao
Kong, Chuize
Watters, Dianne
Johnson, David W.
Gobe, Glenda
Title Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants
Journal name Kidney International  (ERA 2012 Listed)    (ERA 2010 Rank A)   Check publisher's open access policy
Publication date 2005
Sub-type Article
DOI 10.1111/j.1523-1755.2005.00157.x
Volume number 67
Issue number 3
ISSN 0085-2538
Start page 931
End page 943
Total pages 13
Editor S. Klahr
Place of publication Malden, U.S.A.
Publisher Blackwell Publishing Inc.
Collection year 2005
Language eng
Subject C1
730115 Urogenital system and disorders
110312 Nephrology and Urology
Formatted abstract Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by anti-oxidants.

Background
A recent in vitro model of oxidative stress-induced renal fibrosis demonstrated that activated or phosphorylated extracellular signal-regulated protein kinase (pERK) played a role in apoptosis of renal fibroblasts, but not tubular epithelium where it promoted cell growth and survival. The present study utilized an in vivo model of renal fibrosis after unilateral ureteral obstruction (UUO) to examine the relationship between pERK, apoptosis, proliferation, and differentiation in renal fibroblast and tubular epithelial cells, in comparison with the in vitro results.

Methods
UUO was induced in rats for 0 (controls, untreated), 6, and 24 hours, 2, 4, and 7 days (N = 4), and tissue analyzed for fibrotic characteristics using microscopy and special stains, Western immunoblots and reverse transcription-polymerase chain reaction (RT-PCR). Controls and UUO animals were also treated with vitamin E, N-acetylcysteine (NAC), or fluvastatin to assess any antioxidant effect on attenuation of fibrosis and pERK expression.

Results
Azan stain and alpha-smooth muscle actin (alpha-SMA), collagen III, and fibronectin expression confirmed development of UUO-induced fibrosis. Oxidative stress markers heme oxygenase-1 (HO-1) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) confirmed oxidative stress at all UUO time points. Tubular epithelial and interstitial mitosis and apoptosis were significantly increased over controls at 2 to 7 days after UUO (P < 0.01). The pERK/ERK ratio increased significantly at 1 to 7 days of UUO in comparison with controls (three- to fivefold, P < 0.05). There was a significant spatiotemporal correlation between pERK and tubular epithelial proliferation (P < 0.001). pERK occasionally colocalized with apoptotic cells (dual labeling) in the interstitium but not in the tubular epithelium. Fluvastatin was the only treatment that attenuated fibrosis (decreased alpha-SMA, fibronectin, tubular epithelial apoptosis) and it also significantly decreased expression of 8-OHdG at 2 and 7 days (P < 0.05). It was associated with decreased pERK at 7 days, compared with UUO alone (P < 0.05).

Conclusion
Promotion of tubular epithelial proliferation and survival, and interstitial cell apoptosis, may minimize renal fibrosis after UUO. In the present study, both were linked spatially and temporally with increased pERK expression. Fluvastatin treatment attenuated UUO-induced fibrosis via an antioxidant and pERK-related mechanism.
Keyword Urology & Nephrology
Apoptosis
Oxidative Stress
Erk
Renal Fibrosis
Signal Transduction Pathways
Epithelial-myofibroblast Transdifferentiation
Tubulointerstitial Fibrosis
Heme Oxygenase-1
Protein-kinases
Growth-factors
Mouse Kidneys
In-vitro
Experimental Hydronephrosis
Angiotensin-ii
Q-Index Code C1

 
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