title: Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury.
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.
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Sucher
authors.forename: Philipp
authors.initials: P
authors.lastname: Gehwolf
authors.forename: Rupert
authors.initials: R
authors.lastname: Oberhuber
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Christian
authors.initials: C
authors.lastname: Margreiter
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Werner
authors.forename: Peter
authors.initials: P
authors.lastname: Obrist
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneeberger
authors.forename: Robert
authors.initials: R
authors.lastname: Ollinger
authors.forename: Raimund
authors.initials: R
authors.lastname: Margreiter
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D019001:Nitric Oxide Synthase / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D012077:Renal Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015427:Reperfusion Injury / Q000473:pathology; D013481:Superoxides / Q000494:pharmacology
chemical_list: D013481:Superoxides; D030421:Peroxynitrous Acid; D001708:Biopterins; D019001:Nitric Oxide Synthase