The nephroprotective potential of N-acetyl-seryl-aspartyl-lysyl-proline

Abstract

The burden of chronic kidney disease (CKD), which is associated with heightened cardiovascular morbidity and mortality, is rapidly rising. Currently, renin-angiotensin-system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibition or angiotensin II receptor antagonism is the best-documented treatment strategy available to delay CKD progression. However, it remains evident today that many patients with CKD continues to progress relentlessly to end-stage renal failure despite maximal RAS blockade. Thus, there is a pressing unmet need to search for novel therapeutic agents that can effectively abrupt the inflammatory and fibrotic process in response to renal injury.

N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) is an endogenous peptide, with anti-proliferative actions on hematopoietic stem cells, which is released by prolyl oligopeptidase (POP) and exclusively degraded by ACE. The effect of Ac- SDKP to retard the inflammatory and fibrotic process of CKD has not been fully elucidated. The objective of the work presented in this thesis was to evaluate the reno-protective potential of Ac-SDKP by using a unilateral ureteral obstruction (UUO) BALB/C mouse model that recapitulates human CKD.

The UUO mouse model of CKD develops representative tubulointerstitial inflammation by day 3 and fibrosis by day 7. It was shown, in the first in vivo model, that Ac-SDKP treatment was able to down-regulate the expression of profibrotic markers including collagen I (Col1) and collagen III (Col3) induced by UUO. A decreasing trend, albeit statistically insignificant, was also demonstrated for alpha-smooth muscle actin (α-SMA) and the inflammatory mediator monocyte chemoattractant protein-1. These results were paralleled by the treatment with captopril and lent support for the speculation that ACEi may impart reno-protection via Ac-SDKP. In the second in vivo UUO model, it was demonstrated that co-administration of captopril with S17092 (POP inhibitor) abrogated the amelioration of the expression of Col1, Col3, α-SMA and fibronectin by captopril treatment alone. This was reflected in the reversal of the reduction in tubulointerstitial fibrosis and Masson’s trichrome stain uptake on morphological examination. Moreover, down-regulation of the p44/42 mitogen-activated protein kinase signaling pathway by captopril was abolished by co-treatment with S17092.

The results of the experimental studies presented in this thesis suggest that Ac- SDKP harbors reno-protective properties and in particular, demonstrates anti-fibrotic properties that may be effective in CKD. Furthermore, the results gave strong evidence to suggest that the anti-fibrotic benefits conferred by ACE inhibition are mediated by this tetrapeptide. Taken altogether, the data contained herein would support further research aimed at augmenting the level of endogenous Ac-SDKP to provide a novel therapeutic strategy to retard CKD.