title: N-acetyl-seryl-aspartyl-lysyl-proline mediates the anti-fibrotic properties of captopril in unilateral ureteric obstructed BALB/C mice.
abstract: OBJECTIVE
  Angiotensin-converting enzyme inhibitors (ACEi) are widely used to deter the progression of chronic kidney disease (CKD). Besides controlling hypertension and reduction of intra-glomerular pressure, ACEi appear to have anti-fibrotic effects in the renal cortex. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an endogenous tetrapeptide that is degraded by ACE, has also been shown to ameliorate the pro-fibrotic phenotype displayed in CKD in our recent study. Whether the anti-fibrotic properties of ACEi are mediated by Ac-SDKP has not been fully investigated.
  
  
  METHODS
  To delineate the role of Ac-SDKP in ACE blockade, 12-week-old male BALB/c mice underwent sham operation or unilateral ureteric obstruction (UUO). UUO mice were subjected to: (i) vehicle; (ii) captopril or (iii) captopril in conjunction with S17092, a prolyl oligopeptidase inhibitor. After 7 days, mice were sacrificed and kidneys harvested for analyses.
  
  
  RESULTS
  After UUO, there were heightened expressions of collagen I, collagen III, fibronectin and α-SMA associated with significant levels of tubulointerstitial injury on histological examination. Furthermore, p44/42 mitogen-activated protein kinase (MAPK) and transforming growth factor beta 1(TGF-β1) signalling were upregulated. These were significantly ameliorated by captopril treatment alone but unaffected by co-administration of captopril with S17092. Captopril treatment had resulted in elevated urinary Ac-SDKP levels, an effect that was eliminated by the co-administration with S17092.
  
  
  CONCLUSIONS
  This study allowed the investigation of the renoprotective property of ACEi in the absence of Ac-SDKP and proved conclusively that Ac-SDKP is the prime anti-fibrotic mediator of captopril, acting via p44/42 MAPK and TGF-β1 signalling pathways. Future research to expand CKD armamentarium should explore the utility of augmenting Ac-SDKP levels.
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Gary C W
authors.initials: GCW
authors.lastname: Chan
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Hao Jia
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Kam Wa
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Wai Han
authors.initials: WH
authors.lastname: Yiu
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Ailis
authors.initials: A
authors.lastname: Zou
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong.
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong.
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong.
authors.forename: Sydney C W
authors.initials: SCW
authors.lastname: Tang
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D007211:Indoles; D009842:Oligopeptides; C118986:S 17092-1; D015842:Serine Proteinase Inhibitors; C508961:Tgfb1 protein, mouse; D053778:Thiazolidines; D053773:Transforming Growth Factor beta1; D002216:Captopril; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; C058504:goralatide
keywords: Anti-fibrotic; N-acetyl-seryl-aspartyl-lysyl-proline; chronic kidney disease; renoprotection; unilateral ureteric obstruction