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- Title
N-acetyl-seryl-aspartyl-lysyl-proline Mediates the Anti-fibrotic Properties of Captopril in Unilateral Ureteric Obstructed BALB/C Mice.
- Authors
Chan, Gary C. W.; Hao Jia Wu; Kam Wa Chan; Stella Yiu; Ailis Zou; Xiao Ru Huang; Hui Yao Lan; Kar Neng Lai; Tang, Sydney C. W.
- Abstract
Angiotensin-converting enzyme inhibitors (ACEi) are widely employed 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. 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. After UUO, there were heightened expressions of collagen I, collagen III, fibronectin and a-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-ß1) signaling were up-regulated. 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 which was eliminated by the co-administration with S17092. 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-ß1 signaling pathways. Future research to expand CKD armamentarium should explore the utility of augmenting Ac-SDKP levels.
- Subjects
ACE inhibitors; CHRONIC kidney failure; HYPERTENSION; FIBRONECTINS; COLLAGEN; MITOGEN-activated protein kinases
- Publication
Nephrology, 2018, Vol 23, Issue 4, p4
- ISSN
1320-5358
- Publication type
Article
- DOI
10.1111/nep.13000