Abstract: PO2372
Pharmacological Inhibition of Vanin 1 Is Not Protective in Models of Acute and Chronic Kidney Disease
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Unterschemmann, Kerstin Dr., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Ehrmann, Alexander, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Herzig, Ina Daniela, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Andreevski, Anna Lena, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Schmeck, Carsten, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Eitner, Frank, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
- Grundmann, Manuel, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
Background
Dysregulated oxidative stress handling is a hallmark of acute and chronic kidney diseases. The pantetheinase Vanin-1 is highly expressed in tubular cells and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular anti-oxidative glutathione stores. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from acute or chronic kidney injury.
Methods
C57Bl6 mice undergoing ischemia reperfusion injury and Col4α3-/- (Alport syndrome) mice were treated orally for 1d and 3wk, respectively, with a potent and selective Vanin-1 inhibitor or placebo. In vitro oxidative stress insult was mimicked in human renal proximal tubular epithelial cells either chemically or by hypoxia/reoxygenation. Kidney function was determined by serum and urinary creatinine as well as serum urea and urinary albumin. Furthermore, mRNA and protein expression, Vanin-1 activity, oxidative stress level and tubular apoptosis were monitored.
Results
Oxidative stress levels were elevated in all models. Treatment with the Vanin-1 inhibitor resulted in ample systemic compound exposure and full inhibition of Vanin-1 activity in kidney tissue in vivo. However, this did not translate to a relevant reduction of oxidative stress level. Moreover, kidney function (serum Crea, blood urea, albuminuria), fibrosis marker gene expression and tubular cell apoptosis were not improved by Vanin-1 inhibition.
Conclusion
Pharmacological inhibition of Vanin-1 is insufficient to protect kidneys from oxidative stress insults contributing to acute and chronic kidney injury. The biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.
Funding
- Commercial Support –