The study examines the role of toll-like receptor 2 (TLR2)-mediated signals in a murine model of renal ischemia reperfusion (IR) injury. Experimental renal IR injury mimics ischemic acute kidney injury, a major cause of morbidity and mortality in hospitalized patients. The overall HYPOTHESIS to be tested is that TLR2 plays a primary role in the pathogenesis of renal IR injury by directly and/or indirectly contributing to renal tubular cell injury.
Specific Aims : (1) Determine whether TLR2-mediated signals directly injure tubular epithelial cells and define the mechanisms of cell injury;(2) Determine whether TLR2 ligation contributes to IR injury through direct (local) or indirect (systemic) effects;(3) Determine whether TLR2 ligation contributes to IR injury through activation of adaptive immunity. Significance: Ischemia reperfusion injury is a common cause of acute renal failure in hospitalized patients and is directly linked to an increase in morbidity and mortality. Despite extensive research, the mechanisms of renal injury remain elusive and more importantly there are no effective prophylactic regimens or treatments for established disease, other than supportive care. Recognition that ischemic tissue releases molecules that trigger tissue injury through TLRs has opened a new field of research. The PI's laboratory has found that one TLR, TLR2, is highly expressed in the region of the kidney that is most sensitive to renal IR injury. If TLR2 is found to be the key participant in either local or systemic phases of renal IR injury, then TLR2 directed strategies would be pursued for both prophylaxis and treatment of ischemic renal injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Kimmel, Paul
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Scripps Research Institute
La Jolla
United States
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Kasimsetty, Sashi G; Shigeoka, Alana A; Scheinok, Andrew A et al. (2017) Lack of Both Nucleotide-Binding Oligomerization Domain-Containing Proteins 1 and 2 Primes T Cells for Activation-Induced Cell Death. J Immunol 199:1196-1205
DeWolf, Sean E; Shigeoka, Alana A; Scheinok, Andrew et al. (2017) Expression of TLR2, NOD1, and NOD2 and the NLRP3 Inflammasome in Renal Tubular Epithelial Cells of Male versus Female Mice. Nephron 137:68-76
Elahimehr, Reza; Scheinok, Andrew T; McKay, Dianne B (2016) Hematopoietic stem cells and solid organ transplantation. Transplant Rev (Orlando) 30:227-34
Ratigan, Emmett D; McKay, Dianne B (2016) Exploring principles of hibernation for organ preservation. Transplant Rev (Orlando) 30:13-9
Kasimsetty, Sashi G; McKay, Dianne B (2016) Ischemia as a factor affecting innate immune responses in kidney transplantation. Curr Opin Nephrol Hypertens 25:3-11
Kasimsetty, Sashi G; Scheinok, Andrew T; Shigeoka, Alana A et al. (2015) Simultaneous deletion of NOD1 and NOD2 inhibits in vitro alloresponses but does not prevent allograft rejection. Immunobiology 220:1227-31
Kasimsetty, Sashi G; DeWolf, Sean E; Shigeoka, Alana A et al. (2014) Regulation of TLR2 and NLRP3 in primary murine renal tubular epithelial cells. Nephron Clin Pract 127:119-23
Cheung, Kitty P; Kasimsetty, Sashi G; McKay, Dianne B (2013) Innate immunity in donor procurement. Curr Opin Organ Transplant 18:154-60
McKay, Dianne; Jameson, Julie (2012) Kidney transplantation and the ageing immune system. Nat Rev Nephrol 8:700-8
McKay, Dianne B (2011) The role of innate immunity in donor organ procurement. Semin Immunopathol 33:169-84

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