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postgraduate thesis: The nephroprotective potential of N-acetyl-seryl-aspartyl-lysyl-proline
Title | The nephroprotective potential of N-acetyl-seryl-aspartyl-lysyl-proline |
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Authors | |
Issue Date | 2016 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Chan, C. G. [陳志弘]. (2016). The nephroprotective potential of N-acetyl-seryl-aspartyl-lysyl-proline. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
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. |
Degree | Doctor of Philosophy |
Subject | Peptides - Therapeutic use Kidneys - Diseases - Treatment |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/238858 |
HKU Library Item ID | b5824315 |
DC Field | Value | Language |
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dc.contributor.author | Chan, Chi-wang, Gray | - |
dc.contributor.author | 陳志弘 | - |
dc.date.accessioned | 2017-02-20T02:06:42Z | - |
dc.date.available | 2017-02-20T02:06:42Z | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Chan, C. G. [陳志弘]. (2016). The nephroprotective potential of N-acetyl-seryl-aspartyl-lysyl-proline. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/238858 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Peptides - Therapeutic use | - |
dc.subject.lcsh | Kidneys - Diseases - Treatment | - |
dc.title | The nephroprotective potential of N-acetyl-seryl-aspartyl-lysyl-proline | - |
dc.type | PG_Thesis | - |
dc.identifier.hkul | b5824315 | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.mmsid | 991021207299703414 | - |