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 AT1R 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 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 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.
Highlights
Within the kidney, oxidative stress injury to glomerular, tubular, or endothelial cells is the initiating cause of many acute and chronic lesions, leading to progressive dysfunction and endstage renal disease (Lv et al, 2018; Daenen et al, 2019)
Following a 30-mg/kg injection, the maximal concentration of SS-31 was reached after 1 h and was comparable in the plasma, the liver, and the kidney, but the total concentration AUCinf was slightly higher in the kidney compared to the other organs, which is reflected by a longer half-life (T1/2)
Mitochondrial changes are a feature of kidney diseases, suggesting that reducing reactive oxygen species (ROS) generation may be of therapeutic interest
Summary
Oxidative stress injury to glomerular, tubular, or endothelial cells is the initiating cause of many acute and chronic lesions, leading to progressive dysfunction and endstage renal disease (Lv et al, 2018; Daenen et al, 2019). An oxidative stress may be induced by either metabolic disorders and inflammation, such as hypertension and diabetes, or drug toxicity such as radiology contrast agents, antibiotics, and anticancer chemotherapeutics (Hulse and Rosner, 2019). The main organelle producing reactive oxygen species (ROS) is the mitochondria, but other metabolic pathways may produce an oxidative stress and induce various stress responses in the kidney. ROS can either directly damage biological structures or indirectly activate cellular signaling pathways that are deleterious to the normal function of organs. Reducing ROS generation in response to tissue stress may prevent injury to the kidney (Koga et al, 2012). Antioxidants, by scavenging oxidants or by inhibiting oxidative stress pathways, are interesting agents to protect tissues and organs. Active oxygen species are fundamental cellular signaling mediators and effectors, necessary for several important physiological processes
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