Transcriptional analysis of infiltrating T cells in kidney ischemia-reperfusion injury reveals a pathophysiological role for CCR5

Abstract

Ko GJ, Linfert D, Jang HR, Higbee E, Watkins T, Cheadle C, Liu M, Racusen L, Grigoryev DN, Rabb H. Transcriptional analysis of infiltrating T cells in kidney ischemia-reperfusion injury reveals a pathophysiological role for CCR5. Am J Physiol Renal Physiol 302: F762-F773, 2012. First published December 7, 2011; doi:10.1152/ajprenal.00335.2011.-Although T cells have been shown to play a direct role in kidney ischemia-reperfusion injury (IRI), little is known about the underlying mechanisms. We hypothesized that studying the transcriptional responses in kidney-infiltrating T cells would help elucidate novel therapeutic targets for kidney IRI. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6 mice, and CD3(+) T cells were isolated from the kidney and purified. Transcriptional activities of T cell were measured by array-based PCR compared between ischemic kidneys and contralateral nonischemic kidneys. Among total of 89 genes analyzed, 24, 22, 24, and 37 genes were significantly changed at 6 h, day 3, day 10, and day 28 after IRI. Genes associated with cytokines, chemokines, and costimulatory molecules were upregulated. Pathway analysis identified CC motif chemokine receptor 5 (CCR5) as a candidate pathophysiological pathway. CCR5 upregulation was validated at the protein level, and CCR5 blockade improved renal function after kidney IRI. Using discovery techniques to identify transcriptional responses in purified kidney-infiltrating cells enabled the elucidation of novel mechanisms and therapeutic targets for IRI.