Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney

2005 ◽  
Vol 288 (4) ◽  
pp. F778-F784 ◽  
Author(s):  
Christopher A. Adin ◽  
Byron P. Croker ◽  
Anupam Agarwal
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Reaction Products ◽  
Isolated Perfused Rat Kidney ◽  
Organ Systems ◽  
Perfused Rat Kidney

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 have not been investigated in the kidney. The purpose of this study was to evaluate the efficacy and dose-related protective effects of 1 or 10 μM bilirubin flush before a 20-min 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 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 μM 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 pretreatment with micromolar doses of bilirubin may offer a simple and inexpensive method to improve renal function after IRI.

Intravenous bilirubin provides incomplete protection against renal ischemia-reperfusion injury in vivo

2007 ◽  
Vol 292 (2) ◽  
pp. F888-F894 ◽  
Author(s):  
Kristin Kirkby ◽  
Chris Baylis ◽  
Anupam Agarwal ◽  
Byron Croker ◽  
Linda Archer ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Renal Plasma Flow ◽  
In Vivo Model ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Organ Systems

Exogenous bilirubin (BR) substitutes for the protective effects of heme oxygenase (HO) in several organ systems. Our objective was to investigate the effects of exogenous BR in an in vivo model of ischemia-reperfusion injury (IRI) in the rat kidney. Four groups of male Sprague-Dawley rats were anesthetized using isoflurane in oxygen and treated with 1) 5 mg/kg intravenous (iv) BR, 1 h before ischemia and 6-h reperfusion; 2) vehicle 1 h before ischemia and 6-h reperfusion; 3) 20 mg/kg iv BR, 1 h before and during ischemia; and 4) vehicle 1 h before and during ischemia. Bilateral renal clamping (30 min) was followed by 6-h reperfusion. Infusion of 5 mg/kg iv BR achieved target levels in the serum at 6 h postischemia (31 ± 9 μmol/l). Infusion of 20 mg/kg BR reached 50 ± 22 μmol/l at the end of ischemia, and a significant improvement was seen in serum creatinine at 6 h (1.07 ± 28 vs. 1.38 ± 0.18 mg/dl, P = 0.043). Glomerular filtration rate, estimated renal plasma flow, fractional excretion of electrolytes, and renal vascular resistance were not significantly improved in BR-treated groups. Histological grading demonstrated a trend toward preservation of cortical proximal tubules in rats receiving 20 mg/kg iv BR compared with control; however, neither BR dose provided protection against injury to the renal medulla. At the doses administered, iv BR did not provide complete protection against IRI in vivo. Combined supplementation of both BR and carbon monoxide may be required to preserve renal blood flow and adequately substitute for the protective effects of HO in vivo.

Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide

2004 ◽  
Vol 287 (5) ◽  
pp. F979-F989 ◽  
Author(s):  
Joao Seda Neto ◽  
Atsunori Nakao ◽  
Kei Kimizuka ◽  
Anna Jeanine Romanosky ◽  
Donna B. Stolz ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Heme Oxygenase 1 ◽  
Kidney Graft ◽  
Protective Effects ◽  
Tubular Necrosis ◽  
University Of Wisconsin ◽  
Oxide Synthase

Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against oxidative stress. We hypothesized that CO would protect ischemia-reperfusion (I/R) injury of transplanted organs, and the efficacy of CO was studied in the rat kidney transplantation model. A Lewis rat kidney graft, preserved in University of Wisconsin solution at 4°C for 24 h, was orthotopically transplanted into syngeneic rats. Recipients were maintained in room air or exposed to CO (250 ppm) in air for 1 h before and 24 h after transplantation. Animals were killed 1, 3, 6, and 24 h after transplantation to assess efficacy of inhaled CO. Rapid upregulation of mRNA for IL-6, IL-1β, TNF-α, ICAM-1, heme oxygenase-1, and inducible nitric oxide synthase was observed within 3 h after transplantation in the control grafts of air-exposed recipients, associating with histopathological evidences of acute tubular necrosis, interstitial hemorrhage, and edema. In contrast, the increase of inflammatory mediators was markedly inhibited in kidney grafts of CO-treated recipients, which correlated with improved renal cortical blood flow. Further detailed morphological analyses revealed that CO preserved the glomerular vascular architecture and podocyte viability with less apoptosis of tubular epithelial cells and less ED1+ macrophage infiltration. CO inhalation resulted in improved serum creatinine levels and clearance, and animal survival was significantly improved with CO to 60.5 from 25 days in untreated controls. The study demonstrates that exposure of kidney graft recipients to CO at a low concentration can impart significant protective effects against renal I/R injury and improve function of renal grafts.

Protective Effects of Phosphodiesterase-4-specific Inhibitor Rolipram on Acute Ischemia-reperfusion Injury in Rat Kidney

Urology ◽  
2012 ◽  
Vol 80 (6) ◽  
pp. 1390.e1-1390.e6 ◽  
Author(s):  
Emin Mammadov ◽  
Ibrahim Atilla Aridogan ◽  
Volkan Izol ◽  
Arbil Acikalin ◽  
Deniz Abat ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Acute Ischemia ◽  
Protective Effects ◽  
Phosphodiesterase 4

Selective A2A adenosine receptor activation reduces ischemia-reperfusion injury in rat kidney

1999 ◽  
Vol 277 (3) ◽  
pp. F404-F412 ◽  
Author(s):  
Mark D. Okusa ◽  
Joel Linden ◽  
Timothy Macdonald ◽  
Liping Huang
Keyword(s):  
Serum Creatinine ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Receptor Activation ◽  
Protective Effects ◽  
A2a Adenosine Receptor ◽  
Vascular Congestion ◽  
Reperfusion Period

A2A adenosine receptors (A2A-ARs) are known modulators of renal hemodynamics and potent inhibitors of inflammation. We sought to determine whether selective activation of A2A-ARs protects kidneys from ischemia-reperfusion injury. The ester derivative of DWH-146 (DWH-146e), a selective A2A agonist, was found to be more potent and selective for A2A-ARs than the prototype compound CGS-21680. Osmotic minipumps were implanted subcutaneously to infuse into rats either vehicle or DWH-146e (0.004 μg ⋅ kg−1 ⋅ min−1), during and after ischemia-reperfusion injury. Following 24 and 48 h of reperfusion, the rise in serum creatinine and blood urea nitrogen for vehicle-treated rats was substantially elevated compared with DWH-146e-treated rats. Histological examination revealed widespread tubular epithelial necrosis and vascular congestion in the outer medulla of vehicle-treated compared with DWH-146e-treated animals. ZM-241385, a selective A2A antagonist, blocked the protective effect of DWH-146e. Delaying administration of DWH-146e until the initiation of reperfusion also decreased serum creatinine. We conclude that 1) selective A2A-AR activation by DWH-146e reduces ischemia-reperfusion injury in rat kidneys, 2) the effect of DWH-146e is A2A receptor mediated, and 3) the protective effects are mediated by preventing injury during the reperfusion period.

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