Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury

Robert Sucher, Philipp Gehwolf, Rupert Oberhuber, Martin Hermann, Christian Margreiter, Ernst R. Werner, Peter Obrist, Stefan Schneeberger, Robert Ollinger, Raimund Margreiter, Gerald Brandacher

Research output: Contribution to journalArticle

Abstract

Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia-reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans.

Original languageEnglish (US)
Pages (from-to)681-689
Number of pages9
JournalKidney International
Volume77
Issue number8
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Ischemia reperfusion
  • Ischemic renal failure
  • Kidney transplantation
  • Nitric oxide

ASJC Scopus subject areas

  • Nephrology

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    Sucher, R., Gehwolf, P., Oberhuber, R., Hermann, M., Margreiter, C., Werner, E. R., Obrist, P., Schneeberger, S., Ollinger, R., Margreiter, R., & Brandacher, G. (2010). Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury. Kidney International, 77(8), 681-689. https://doi.org/10.1038/ki.2010.7