Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease.
Am J Physiol Renal Physiol
; 320(1): F61-F73, 2021 01 01.
Article
in En
| MEDLINE
| ID: mdl-33196323
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. Although 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 have gained 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 antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. 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 in Col4α3-/- (Alport syndrome) mice and in vitro hypoxia-reoxygenation in 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 investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Reperfusion Injury
/
Oxidative Stress
/
Enzyme Inhibitors
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Renal Insufficiency, Chronic
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Acute Kidney Injury
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Amidohydrolases
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Kidney Tubules, Proximal
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Nephritis, Hereditary
Language:
En
Journal:
Am J Physiol Renal Physiol
Journal subject:
FISIOLOGIA
/
NEFROLOGIA
Year:
2021
Document type:
Article
Affiliation country:
Germany