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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Centre for Experimental Medicine, Nephrology, and Critical Care, William Harvey Research Institute, Queen Mary, University of London, London, United Kingdom (N.S.A.P., C.T.); Department of Pharmacology and Therapeutics, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom (P.K.C.); Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy (R.D.P., E.M., A.D.S., S.C.); and Department of Veterinary and Agricultural Science, University of Teramo, Teramo, Italy (D.B.)
Here, we investigate the effects of renal ischemia/reperfusion (I/R) on the degree of renal injury, dysfunction, and inflammation in interleukin (IL)-6 knockout (IL-6-/-) mice and mice administered a monoclonal antibody against IL-6. IL-6-/- mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (24 h). At the end of experiments, indicators and markers of renal dysfunction, injury, and inflammation were measured. Kidneys were used for histological evaluation of renal injury. Renal expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and P-selectin, as well as nitration of proteins in the kidney, were determined using immunohistochemistry. In addition, wild-type mice were pretreated (24 and 1 h before ischemia) with an IL-6 antibody to mimic the effects that would be seen in IL-6-/- mice. IL-6-/- mice and wild-type mice administered the IL-6 antibody demonstrated significantly reduced plasma urea and creatinine levels, indicating reduction of renal dysfunction caused by I/R. Neutrophil infiltration was also significantly reduced in IL-6-/- mice and wild-type mice administered the IL-6 antibody subjected to renal I/R. Proinflammatory cytokines (tumor necrosis factor-
and IL-1
) in renal tissues were significantly attenuated in IL-6-/- mice to levels seen in wild-type mice. IL-6-/- mice demonstrated reduced histological evidence of tubular injury and markedly reduced immunohistochemical evidence of ICAM-1, P-selectin, and nitrotyrosine when subjected to renal I/R. We propose that endogenous IL-6 enhances the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules and subsequent oxidative and nitrosative stress.
Address correspondence to: Prof. Christoph Thiemermann, Centre for Experimental Medicine, Nephrology, and Critical Care, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK. E-mail: c.thiemermann{at}qmul.ac.uk
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