Perioperative acute renal failure is a devastating complication with high mortality. Ischemia and reperfusion injury is a frequent cause of perioperative acute renal failure. We demonstrated during the first funding period that A1 adenosine receptor (AR) activation acutely protected against necrotic renal IR injury and reduced inflammation and apoptosis after IR injury in vivo via mechanisms involving Gi, ERK and PKC. This competitive renewal proposes to continue the investigation of the mechanisms of renal protection with A1 adenosine receptors (ARs) against ischemia reperfusion induced acute renal failure. Preliminary data generated suggest that the renal protection with A1AR activation appeared to be biphasic: acute renal protection waned 3-4 hrs after treatment but re-appeared about 16 hrs after initial treatment with A1 AR agonists. This phenomenon has never been described in the kidney prior to this application. Exciting preliminary data generated also suggest important roles for Akt and heat shock protein 27 (HSP27) phosphorylation and cytoskeletal filamentous actin (F-actin) stabilization to mediate acute renal protection following A1AR activation whereas induction of new HSP27 protein mediates the delayed renal protection following A1AR activation. These findings lead use to hypothesize that A1AR activation produces biphasic (early and delayed) renal protection via different cellular mechanisms: the early phase of renal protection involves HSP27 phosphorylation while the late phase of renal protection requires de novo HSP27 protein synthesis. To address this hypothesis, we have formulated the following 3 aims:
Aim #1 : To identify the signaling pathways by which A1 AR activation mediates early renal protection.
Aim #2 : To define the signal transduction pathways that mediate delayed renal protection following A1 AR activation.
Aim #3 : To determine the therapeutic benefit of modulating the acute and delayed signaling events initiated by A1 AR activation in vivo and in vitro. To test these aims, we will utilize both in vivo and in vitro models of IR injury. In vivo studies will involve well characterized renal IR injury in mice. For in vitro studies, we will use freshly isolated proximal tubules from A1WT and A1KO mice as well as human proximal tubule cells in culture. Our proposed research integrates whole animal, molecular, histblogical as well as biochemical techniques to aid in a better understanding of the cellular mechanisms of acute renal failure during and after IR injury. This, in turn, will contribute to improved therapeutic regimens for the protection of renal function in patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058547-09
Application #
7646513
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kimmel, Paul
Project Start
2001-03-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
9
Fiscal Year
2009
Total Cost
$282,663
Indirect Cost
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Rabadi, May; Kim, Mihwa; D'Agati, Vivette et al. (2016) Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion. Am J Physiol Renal Physiol 311:F437-49
Rabadi, M M; Lee, H T (2015) Adenosine receptors and renal ischaemia reperfusion injury. Acta Physiol (Oxf) 213:222-31
McIlroy, David R; Farkas, David; Matto, Matthew et al. (2015) Neutrophil gelatinase-associated lipocalin combined with delta serum creatinine provides early risk stratification for adverse outcomes after cardiac surgery: a prospective observational study. Crit Care Med 43:1043-52
Ham, Ahrom; Rabadi, May; Kim, Mihwa et al. (2014) Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 307:F1052-62
Ham, Ahrom; Kim, Mihwa; Kim, Joo Yun et al. (2014) Selective deletion of the endothelial sphingosine-1-phosphate 1 receptor exacerbates kidney ischemia-reperfusion injury. Kidney Int 85:807-23
Kim, Joo Yun; Kim, Mihwa; Ham, Ahrom et al. (2013) IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI. J Am Soc Nephrol 24:1558-70
Ham, Ahrom; Kim, Mihwa; Kim, Joo Yun et al. (2013) Critical role of interleukin-11 in isoflurane-mediated protection against ischemic acute kidney injury in mice. Anesthesiology 119:1389-401
Bakar, Adnan M; Park, Sang Won; Kim, Mihwa et al. (2012) Isoflurane protects against human endothelial cell apoptosis by inducing sphingosine kinase-1 via ERK MAPK. Int J Mol Sci 13:977-93
Park, Sang Wong; Kim, Mihwa; Brown, Kevin M et al. (2012) Inhibition of sphingosine 1-phosphate receptor 2 protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 23:266-80
Park, Sang W; Kim, Mihwa; Kim, Joo Y et al. (2012) Proximal tubule sphingosine kinase-1 has a critical role in A1 adenosine receptor-mediated renal protection from ischemia. Kidney Int 82:878-91

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