The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby caspase-1 and caspase-1-related cytokines like IL-18 and IL-1a lead to increased macrophage and NK cell infiltration in the kidney and resultant ischemic acute renal failure (ARF). Novel published data demonstrating that impaired IL-18 processing protects caspase-1 deficient mice from ischemic ARF supports the hypothesis. Complementary studies in mice will be performed in different models: 1) ischemic ARF in vivo, 2) freshly isolated renal proximal tubules in suspension and 3) microvascular endothelial cells in culture.
In Specific Aim 1, the time course of increased caspase-1 and IL-18 expression in ischemic ARF will be determined. In addition, the therapeutic potential of newly developed caspase-1 and IL-18 inhibitors will be tested. Fractalkine is a major chemoattractant for macrophages and NK cells.
In Specific Aim 2, we shall determine whether there is a cytokine-mediated increase of fractalkine in the endothelium.
Specific Aim 3 focuses on macrophages and NK cells as sources of caspase-1, IL-18, IL-1a and other cytokines in ischemic ARF. In vivo studies using inhibitors of macrophages and NK cells will test the potential for clinical application. Activated macrophages and NK cells stimulated by IL-18 are known to mediate cell lysis via perforin and/or granzymes.
In Specific Aim 4, we propose that IL-18-dependent or independent production of perforin and gzmA by macrophages and NK cells contributes to FT injury (in vitro) and ATN (in vivo). The relevance of these studies to clinical ARF is substantial. The results should provide new insights into the pathophysiology of ischemic ARF as well as leads to altering the course of ischemic ARF. This is particularly true because of the current availability of caspase-1 and IL-18 inhibitors e.g. pralnacasan and IL-18 binding protein (IL-18 BP) that are being tested in clinical trials.
|Kim, Hyun-Jung; Lee, Dong Won; Ravichandran, Kameswaran et al. (2013) NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury. J Pharmacol Exp Ther 346:465-72|
|Huber, Tobias B; Edelstein, Charles L; Hartleben, Bjorn et al. (2012) Emerging role of autophagy in kidney function, diseases and aging. Autophagy 8:1009-31|
|Andres-Hernando, Ana; Dursun, Belda; Altmann, Christopher et al. (2012) Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy. Nephrol Dial Transplant 27:4339-47|
|Lu, Lawrence; Faubel, Sarah; He, Zhibin et al. (2012) Depletion of macrophages and dendritic cells in ischemic acute kidney injury. Am J Nephrol 35:181-90|
|Jani, Alkesh; Epperson, Elaine; Martin, Jessica et al. (2011) Renal protection from prolonged cold ischemia and warm reperfusion in hibernating squirrels. Transplantation 92:1215-21|
|Lee, D W; Faubel, S; Edelstein, C L (2011) Cytokines in acute kidney injury (AKI). Clin Nephrol 76:165-73|
|Akcay, Ali; Nguyen, Quocan; He, Zhibin et al. (2011) IL-33 exacerbates acute kidney injury. J Am Soc Nephrol 22:2057-67|
|Turkmen, Kultigin; Martin, Jessica; Akcay, Ali et al. (2011) Apoptosis and autophagy in cold preservation ischemia. Transplantation 91:1192-7|
|Jani, Alkesh; Zimmerman, Michael; Martin, Jessica et al. (2011) Perfusion storage reduces apoptosis in a porcine kidney model of donation after cardiac death. Transplantation 91:169-75|
|Belibi, Franck A; Edelstein, Charles L (2010) Novel targets for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Investig Drugs 19:315-28|
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