Acute kidney injury (AKI) due to renal ischemia and reperfusion (IR) is a major clinical problem without effective therapy. It is estimated that ~$10 billion per year is spent treating AKI in the United States. Exciting and novel preliminary data generated for this proposal suggest that A1AR activation stimulates sphingosine kinase-1 (SK1) enzyme activity in renal proximal tubule and endothelial cells to increase sphingosine 1- phosphate (S1P) generation. Additional preliminary data suggest a crucial role of SK1 and S1P1 receptors in mediating the renal protective effects following A1AR activation. These findings mechanistically link together for the first time two cytoprotective signaling pathways (A1AR and SK1) leading us to hypothesize that A1ARs protect against renal IR via phosphorylation as well as upregulation of SK-1 in renal proximal tubule and endothelial cells. We hypothesize that enhanced S1P synthesis subsequently activates S1P1 receptors in renal proximal tubules, endothelial cells and T-lymphocytes infiltrating the kidney to attenuate renal IR injury. To address this hypothesis, we have formulated the following 3 aims:
Aim #1 : To determine that SK1 and S1P1 receptor signaling is necessary for A1AR-mediated renal protection.
Aim #2 : To define signaling pathways mediating A1AR-stimulation of SK1 and S1P synthesis in renal proximal tubule and endothelial cells.
Aim #3 : To design A1AR and SK1-S1P-based renal protective strategies against IR injury without systemic side effects of A1AR agonist treatment. To test these aims, we will utilize both in vivo (murine renal IR) and in vitro (primary cultures and immortalized proximal tubule and endothelial cell lines) models of IR injury to elucidate the mechanisms of A1AR-mediated SK1 modulation and enhanced S1P synthesis. Cre-lox mouse technology will allow us to selectively delete key signaling intermediates in specific cell types (proximal tubule, endothelial or leukocytes) to further define the role of SK1 and S1P1 receptors in A1AR-mediated renal protection. Our proposed novel research integrates whole animal, molecular, histological as well as biochemical techniques, enabling a new understanding of the mechanisms of A1AR-mediated reduction in renal inflammation, necrosis and apoptosis. This, in turn, will contribute to improved therapeutic regimens for the protection of renal function in patients. As SK1 signaling controls numerous physiological effects including tissue injury, inflammation and immune response in many organs, our findings of A1AR-mediated S1P modulation represent a significant paradigm shift with significant implications for organ protection beyond renal IR injury.

Public Health Relevance

The central hypothesis of this proposal is that A1 adenosine receptor activation reduces all 3 components of renal injury (apoptosis, necrosis and inflammation) via stimulation of sphingosine kinase-1 and activation of sphingosine 1-phosphate 1 receptors. Specifically, we will 1) conclusively define that A1AR-mediated renal protection is dependent on SK1 and S1P signaling, 2) determine the mechanisms of A1AR-mediated SK1 activation and enhanced S1P synthesis and 3) design A1AR-based renal protective strategies against IR injury. Our studies test major novel concepts and provide potential paradigm shifts with immediate clinical translatability. Success of our aims offers a new therapeutic approach to reduce the clinical perils from AKI and have implications in organ protection strategies beyond the kidney.

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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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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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
Park, Sang Won; Kim, Mihwa; Kim, Joo Yun et al. (2012) Paneth cell-mediated multiorgan dysfunction after acute kidney injury. J Immunol 189:5421-33
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

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