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1 Department of Small Animal Clinical Sciences, University of Florida, Gainesville, Florida, USA
2 Department of Pathology, Immunology and Laboratory Medicine and Malcolm Randall VA Service, University of Florida, Gainesville, Florida, USA
3 Department of Medicine, Division of Nephrology, University of Alabama, Birmingham, Birmingham, Alabama, USA
* To whom correspondence should be addressed. E-mail: Adinc{at}mail.vetmed.ufl.edu.
Heme oxygenase-1 (HO-1) is induced as an adaptive and protective response to tissue injury. HO-1 degrades heme into carbon monoxide (CO) and biliverdin; the latter is then converted to bilirubin. These reaction products have powerful antiapoptotic and antioxidant effects. Manipulation of the HO-1 system by administration of micromolar doses of exogenous CO or bilirubin has been performed in several organ systems, but the dose related effects of these reaction products has not been investigated in the kidney. The purpose of this study was to evaluate the efficacy and dose-related protective effects of 1 µM or 10 µM bilirubin flush prior to a 20-minute period of warm ischemia. In an effort to minimize interactions with other chemical messengers or organ systems, we elected to use an isolated perfused rat kidney model (IPRK) with an acellular, oxygenated perfusate. Using this model we demonstrated that bilirubin treatment resulted in significant improvements in renal vascular resistance, urine output, glomerular filtration rate, tubular function and mitochondrial integrity after ischemia-reperfusion injury (IRI). Beneficial effects on organ viability were achieved most consistently with a dose of 10 uM bilirubin. We conclude that the protective effects of HO-1 activity during IRI in the kidney are mediated, at least in part, by bilirubin and that pre-treatment with micromolar doses of bilirubin may offer a simple and inexpensive method to improve renal function after IRI.
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