title: Intermedin is upregulated and attenuates renal fibrosis by inhibition of oxidative stress in rats with unilateral ureteral obstruction.
abstract: OBJECTIVE
  Transforming growth factor-β1 (TGF-β1) plays a pivotal role in the progression of renal fibrosis. Reactive oxygen species mediate profibrotic action of TGF-β1. Intermedin (IMD) has been shown to inhibit oxidative stress, but its role in renal fibrosis remains unclear. Here, we investigated the effects of IMD on renal fibrosis in a rat model of unilateral ureteral obstruction (UUO).
  
  
  METHODS
  The expression of IMD and its receptors, calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP1/2/3), in the obstructed kidney was detected by real-time polymerase chain reaction (PCR), western blotting and immunohistochemistry. To evaluate the effects of IMD on renal fibrosis, we locally overexpressed exogenous IMD in the obstructed kidney using an ultrasound-microbubble-mediated delivery system. Renal fibrosis was determined by Masson trichrome staining. The expression of TGF-β1, connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA) and fibronectin was measured. Smad2/3 activation and macrophage infiltration were evaluated. We also studied oxidative stress by measuring superoxide dismutase (SOD) activity and malondialdehyde (MDA) content.
  
  
  RESULTS
  mRNA and protein expression of IMD increased after UUO. CRLR, RAMP1, RAMP2 and RAMP3 were also induced by ureteral obstruction. IMD overexpression remarkably attenuated UUO-induced tubular injury and blunted fibrotic response as shown by decreased interstitial collagen deposition and downregulation of fibronectin. Macrophage infiltration, α-SMA and CTGF upregulation caused by UUO were all relieved by IMD, whereas TGF-β1 upregulation and Smad2/3 activation were not affected. Meanwhile, we noted increased oxidative stress in obstruction, which was also attenuated by IMD gene delivery.
  
  
  CONCLUSIONS
  Our results indicate that IMD is upregulated after UUO. IMD plays a protective role in renal fibrosis via its antioxidant effects.
authors.affiliation: Department of Nephrology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.|Shanxi Kidney Disease Institute, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Department of Nephrology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.|Shanxi Kidney Disease Institute, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Ruijing
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Weixia
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Nephrology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.|Shanxi Kidney Disease Institute, Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Peng
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D045423:Microbubbles; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D058262:Receptor Activity-Modifying Protein 1 / Q000235:genetics / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014465:Ultrasonics; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: C499411:Adm2 protein, rat; D058286:Calcitonin Receptor-Like Protein; C545580:Calcrl protein, rat; D005353:Fibronectins; D009479:Neuropeptides; D012333:RNA, Messenger; C545508:Ramp1 protein, rat; C545509:Ramp2 protein, rat; C545510:Ramp3 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D053607:Adrenomedullin; D003094:Collagen
keywords: calcitonin receptor-like receptor; intermedin; oxidative stress; receptor activity-modifying proteins; renal fibrosis