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Abstract: PO2372

Pharmacological Inhibition of Vanin 1 Is Not Protective in Models of Acute and Chronic Kidney Disease

Session Information

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