Atorvastatin ameliorates tissue damage of obstructed ureter in rats Yen-Hwang Chuang a, b , Wan-Long Chuang c, d , Shu-Pin Huang e, f , Ching-Kuan Liu g, b , Chun-Hsiung Huang e, f, ⁎ a Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan c Department of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan d Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan e Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan f Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan g Department of Neurology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan abstract article info Article history: Received 20 January 2011 Accepted 13 September 2011 Keywords: Apoptosis Atorvastatin IL-1β IL-6 Obstructive uropathy TGF-β 1 Aims: To investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor on the tissue damage and fibrosis of obstructed ureters, 80 rats were studied. Main methods: Atorvastatin, a HMG-CoA reductase inhibitor, was administered to 40 rats at the dose of 20 mg/kg per day 1 day before unilateral ligation of ureters and every day thereafter. The other rats served as controls. Eight rats from each group were sacrificed for examination on days 7, 14, 21, 28 and 42 after ligation, respectively. The expressions of transforming growth factor-β 1 (TGF-β 1 ), Interleukine-1β (IL-1β), Interleukine-6 (IL-6), tumor necrosis factor-alpha (TNF-α), proliferation cell nuclear antigen (PCNA), and the apoptotic cells in the ureteric smooth muscle were examined. Key findings: Hydroureter and fibrosis of the muscle layer became progressively aggravated in the ligated ureters of the atorvastatin-treated group and control group. The severities of hydroureter and muscle layer fibrosis in the ligated ureters of the treated group were significantly less than in the control group. The ator- vastatin administration also decreased the expression of TGF-β 1 , IL-1β, IL-6, TNF-α, PCNA and the labeling index of apoptotic cells in the smooth muscle layer of ligated ureters in the treated group. Significance: We concluded that atorvastatin might ameliorate the tissue damage of obstructed ureters, at least partially, via the inhibition on TGF-β 1 expression and by diminishing the effects of pro-inflammatory cytokines. © 2011 Elsevier Inc. All rights reserved. Introduction 3-hydroxy-3-methyl glutaryl coenzyme (A HMG-Co A) reductase inhibitors, a class of drugs known as statins, are competitive inhibitors of HMG-Co A reductase that work by suppressing the conversion of HMG-CoA (Liao and Lufs, 2005; Shitara and Sugiyama, 2006; Veillard and Mach, 2002). Statins were initially described as lipid-lowering drugs (Shitara and Sugiyama, 2006; Veillard and Mach, 2002), and the administration of statins significantly decreases cardiovascular morbidity and mortality (Shitara and Sugiyama, 2006; Weitz- Schmidt, 2002). Statins might lower the intracellular levels of isopre- noids and prevent the catabolism of other isoprenoid intermediates of the cholesterol biosynthetic pathway (Haslinger-Loffler, 2008; Liao and Lufs, 2005; Shitara and Sugiyama, 2006; Veillard and Mach, 2002). The isoprenoids are necessary for the post-translational lipid prenylation of a variety of proteins including the small guanosine triphosphate (GTP)-binding proteins (Liao and Lufs, 2005; Weitz- Schmidt, 2002). The GTP-binding proteins are involved in the signal transduction pathways that regulate cell proliferation, cell differentia- tion and apoptosis (Weitz-Schmidt, 2002). In addition, statins have also been shown to have anti-inflammatory, anti-proliferation and immunomodulatory actions in vitro and in vivo (Haslinger-Loffler, 2008; Liao and Lufs, 2005; Sakamoto et al., 2005; Veillard and Mach, 2002; Weitz-Schmidt, 2002). Many of these cholesterol-independent effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates (Haslinger-Loffler, 2008; Liao and Lufs, 2005; Sakamoto et al., 2005; Shitara and Sugiyama, 2006; Veillard and Mach, 2002; Weitz-Schmidt, 2002). Obstructive uropathy caused by ureteric obstruction is one of the most common diseases in the urinary tract. It may lead to severe renal and ureteric injury (Chuang et al., 1995; Chuang et al., 1998; Pais et al., 2007). The aggravation of hydronephrosis results in tubulo-interstitial fibrosis in the kidney, replacement of the renal parenchyma with scar Life Sciences 89 (2011) 795–805 ⁎ Corresponding author at: Department of Urology, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd., Kaohsiung, Taiwan. Tel.: + 886 7 3121101x6694; fax: + 886 7 3218309. E-mail address: yehwch@cc.kmu.edu.tw (C.-H. Huang). 0024-3205/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2011.09.010 Contents lists available at SciVerse ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie