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N‐acetyl‐seryl‐aspartyl‐lysyl‐proline mediates the anti‐fibrotic properties of captopril in unilateral ureteric obstructed BALB/C mice
Author(s) -
Chan Gary C.W.,
Wu Hao Jia,
Chan Kam Wa,
Yiu Wai Han,
Zou Ailis,
Huang Xiao Ru,
Lan Hui Yao,
Lai Kar Neng,
Tang Sydney C.W.
Publication year - 2018
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1111/nep.13000
Subject(s) - captopril , medicine , endocrinology , angiotensin converting enzyme , kidney , renal cortex , pharmacology , blood pressure
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.