N-acetyl-seryl-aspartyl-lysyl-proline mediates the anti-fibrotic properties of captopril in unilateral ureteric obstructed BALB/C mice

Gary C.W. Chan, Hao Jia Wu, Kam Wa Chan, Wai Han Yiu, Ailis Zou, Xiao Ru Huang, Hui Yao Lan, Kar Neng Lai, Sydney C.W. Tang*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

9 Citations (Scopus)


Aim: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)297-307
Number of pages11
Issue number4
Early online date8 Mar 2018
Publication statusPublished - Apr 2018

Scopus Subject Areas

  • Medicine(all)
  • Nephrology

User-Defined Keywords

  • Anti-fibrotic
  • chronic kidney disease
  • N-acetyl-seryl-aspartyl-lysyl-proline
  • renoprotection
  • unilateral ureteric obstruction


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