- acute kidney injury
- renal transplant rejection
- the role of inflammation in chronic kidney disease
Ischemic acute kidney injury (AKI - previously called "acute renal failure" or "acute tubular necrosis") affects approximately 25 percent of ICU patients. AKI confronts the physician with major clinical problems, and the scientist with fundamental unsolved questions. The physician is confronted by a disease with no accepted treatment other than supportive care such as dialysis. The acute mortality and morbidity remains high, and the longterm problems include progressive chronic kidney disease and longterm mortality. The scientist is confronted by a disease where the underlying pathophysiology is not understood. Although it is now recognized that the initial insult to the kidney is exacerbated by a maladaptive inflammatory response, how injury is translated into inflammation remains a fundament unsolved problem.
Furthermore, ischemic AKI inevitably occurs during the process of renal transplantation - the donor hypotension, cold storage, and the transplant surgery. The inflammatory response to this allograft ischemia will include recipient leukocytes that should exacerbate allograft rejection. Thus, our studies will also help us understand and treat allograft rejection. (See Figure 1.)
The overall goal of our laboratory is to elucidate this unsolved problem in the hope that this will led to more effective therapies. To this end, we use in vivo models of ischemic AKI in mice, and in vitro model systems to perform detailed studies of proinflammatory genes activated by renal ischemia/ reperfusion. We have found that molecules, normally residing within healthy cells, are released into the extracellular space when renal cells are injured by ischemia in vivo and in vitro. These molecules elicit activate proinflammatory genes (see Figure 2). In addition, we study the effects of reactive oxygen species, produced during ischemia-reperfusion, on proinflammatory genes.
We are also translating this bench research to the bedside by studying pre-transplant renal biopsies; these biopsy studies will determine if the genes associated with the inflammatory response to ischemia in mice also are activated in man. In addition to addressing fundamental questions, these clinical studies may predict the course and guide therapy of renal transplant recipients.
P. D. Winterberg, Y. Wang, K. M. Lin, J. R. Hartono, G. T. Nagami, X. J. Zhou, J. M. Shelton, J. A. Richardson and C. Y. Lu. Reactive-oxygen species (ROS) and IRF1 stimulate IFNalpha production by proximal tubules during ischemic AKI. Am J Physiol Renal Physiol. 2013;305(2):F162-72. Epub 2013/05/10.
J. Chen, M. M. Matzuk, X. J. Zhou and C. Y. Lu. Endothelial pentraxin 3 contributes to murine ischemic acute kidney injury. Kidney Int. 2012;82:1195-1207.
J. Chen, R. John, J. A. Richardson, J. M. Shelton, X. J. Zhou, Y. Wang, Q. Q. Wu, J. R. Hartono, P. D. Winterberg and C. Y. Lu. Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury. Kidney Int. 2011;79(3):288-99.
J. Chen, J. Hartono, R. John, M. Bennett, X. Zhou, Y. Wang, Q. Wu, P. Winterberg, G. T. Nagami and C. Y. Lu. Interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4. Kidney Int. 2011;80(5):504-15.
Q. Q. Wu, Y. Wang, M. Senitko, C. Meyer, W. C. Wigley, D. A. Ferguson, E. Grossman, J. Chen, X. J. Zhou, J. Hartono, P. Winterberg, B. Chen, A. Agarwal and C. Y. Lu. Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARgamma, and HO-1. Am J Physiol Renal Physiol. 2011;300(5):F1180-92.
Y. Wang, R. John, J. Chen, J. A. Richardson, J. M. Shelton, M. Bennett, X. J. Zhou, G. T. Nagami, Y. Zhang, Q. Q. Wu and C. Y. Lu. IRF-1 promotes inflammation early after ischemic acute kidney injury. J Am Soc Nephrol 20:1544-55.
C. Y. Lu, P. D. Winterberg, J. Chen and J. R. Hartono. Acute kidney injury: a conspiracy of toll-like receptor 4 on endothelia, leukocytes, and tubules. Pediatr Nephrol. 2012;27:1847-54.
C. Y. Lu, J. Hartono, M. Senitko and J. Chen. The inflammatory response to ischemic acute kidney injury: a result of the 'right stuff' in the 'wrong place'? Curr Opin Nephrol Hypertens 2007;16(2):83-9. Epub 2007/02/13.
C. Y. Lu, J. G. Penfield, M. L. Kielar, M. A. Vazquez and D. R. Jeyarajah. Perspectives in basic science: Hypothesis: is renal allograft rejection initiated by the response to injury sustained during the transplant process? Kidney Int 1999;55:2157-2168.
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