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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01209

Differential responses to peptidase-targeted prodrugs of the mitochondria-active tetrapeptide SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2) in experimental acute renal injury

 Dela Golshayan1, 2, 3*,  Jean-Christophe Wyss3, Lucienne Juillerat-Jeanneret2, 3,  Rajesh Kumar3, 4, Johannes Aebi5, Manfred Schneider5 and Jean-Luc Mary5
  • 1Lausanne University Hospital (CHUV), Switzerland
  • 2Université de Lausanne, Switzerland
  • 3Laboratoire d'immunopathologie de transplantation, Centre Hospitalier Universitaire Vaudois (CHUV), Switzerland
  • 4Dana–Farber Cancer Institute, United States
  • 5Roche (Switzerland), Switzerland

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 regulation of the Ang receptors and APA by SS-31 was further investigated using real-time qPCRs performed on mRNAs extracted from diseased kidneys. Following acute tubular and/or glomerular damage, the expression of the AT1R mRNA was upregulated, which could be selectively down-regulated upon SS-31 administration to the animals. At the same time, SS-31 was able to increase the expression of the AT2R, 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 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: Oxidatative stress, Aminopeptidase A, Renin- angiotensin system, experimental - animal models, Acute renal injury

Received: 15 Jun 2019; Accepted: 20 Sep 2019.

Copyright: © 2019 Golshayan, Wyss, Juillerat-Jeanneret, Kumar, Aebi, Schneider and Mary. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Dela Golshayan, Lausanne University Hospital (CHUV), Lausanne, 1011, Vaud, Switzerland, dela.golshayan@chuv.ch