Differential Effects of the Mitochondria-Active Tetrapeptide SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH<sub>2</sub>) and Its Peptidase-Targeted Prodrugs in Experimental Acute Kidney Injury.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_50D20D70B14C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Differential Effects of the Mitochondria-Active Tetrapeptide SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH<sub>2</sub>) and Its Peptidase-Targeted Prodrugs in Experimental Acute Kidney Injury.
Journal
Frontiers in pharmacology
Author(s)
Wyss J.C., Kumar R., Mikulic J., Schneider M., Mary J.L., Aebi J.D., Juillerat-Jeanneret L., Golshayan D.
ISSN
1663-9812 (Print)
ISSN-L
1663-9812
Publication state
Published
Issued date
2019
Peer-reviewed
Oui
Volume
10
Pages
1209
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
The mitochondria-active tetrapeptide SS-31 can control oxidative tissue damage in kidney diseases. To investigate other potential beneficial nephroprotective effects of SS-31, in vivo murine models of acute tubular injury and glomerular damage were developed. Reduction of acute kidney injury was demonstrated in mice treated with SS-31. The expression of mRNAs involved in acute inflammatory and oxidative stress responses in the diseased kidneys confirmed that SS-31 could regulate these pathways in our in vivo models. Furthermore, ex vivo histoenzymography of mouse kidneys showed that aminopeptidase A (APA), the enzyme involved in the processing of angiotensin (Ang) II to Ang III, was induced in the diseased kidneys, and its activity was inhibited by SS-31. As the renin-angiotensin system (RAS) is a main regulator of kidney functions, the modulation of Ang receptors (ATR) and APA by SS-31 was further investigated using mRNAs extracted from diseased kidneys. Following acute tubular and/or glomerular damage, the expression of the AT <sub>1</sub> R mRNA was upregulated, which could be selectively downregulated upon SS-31 administration to the animals. At the same time, SS-31 was able to increase the expression of the AT <sub>2</sub> R, which may contribute to limit renal damage. Consequently, SS-31-based prodrugs were developed as substrates and/or inhibitors for APA and were screened using cells expressing high levels of APA, showing its selective regulation by α-Glu-SS-31. Thus, a link between SS-31 and the RAS opens new therapeutic implications for SS-31 in kidney diseases.
Keywords
acute renal injury, aminopeptidase A, experimental kidney disease, oxidative stress, renin–angiotensin system
Pubmed
Web of science
Open Access
Yes
Create date
02/12/2019 10:14
Last modification date
17/04/2020 6:08
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