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Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease

Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney... Oxidative stress is a key concept in basic, translational and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. While attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically gain further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular anti-oxidative glutathione stores. Vanin-1 deficient mice were shown to be protected against various oxidative stress damages. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress related acute or chronic kidney injury as well. By studying renal ischemia reperfusion injury and Col4α3-/- (Alport syndrome) mice and in vitro hypoxia/reoxygenation on human proximal tubular cells we found that treatment with a selective and potent Vanin‑1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigations and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Physiology-Renal Physiology The American Physiological Society

Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease

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References (47)

ISSN
1931-857x
eISSN
1522-1466
DOI
10.1152/ajprenal.00373.2020
Publisher site
See Article on Publisher Site

Abstract

Oxidative stress is a key concept in basic, translational and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. While attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically gain further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular anti-oxidative glutathione stores. Vanin-1 deficient mice were shown to be protected against various oxidative stress damages. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress related acute or chronic kidney injury as well. By studying renal ischemia reperfusion injury and Col4α3-/- (Alport syndrome) mice and in vitro hypoxia/reoxygenation on human proximal tubular cells we found that treatment with a selective and potent Vanin‑1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigations and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.

Journal

American Journal of Physiology-Renal PhysiologyThe American Physiological Society

Published: Jan 1, 2021

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