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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058547-13
Application #
8470623
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kimmel, Paul
Project Start
2001-03-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$335,821
Indirect Cost
$125,933
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
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
Yap, Steven C; Lee, H Thomas (2012) Adenosine and protection from acute kidney injury. Curr Opin Nephrol Hypertens 21:24-32
Kim, Minjae; Park, Sang Won; Kim, Mihwa et al. (2012) Isoflurane post-conditioning protects against intestinal ischemia-reperfusion injury and multiorgan dysfunction via transforming growth factor-?1 generation. Ann Surg 255:492-503
Park, Sang Won; Chen, Sean W C; Kim, Mihwa et al. (2011) Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab Invest 91:63-84
Park, Sang Won; Kim, Minjae; Kim, Mihwa et al. (2011) Sphingosine kinase 1 protects against renal ischemia-reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation. Kidney Int 80:1315-27
Kim, Minjae; Park, Sang Won; Kim, Mihwa et al. (2011) Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction. Am J Physiol Renal Physiol 300:F167-76
Park, Sang Won; Kim, Mihwa; Brown, Kevin M et al. (2011) Paneth cell-derived interleukin-17A causes multiorgan dysfunction after hepatic ischemia and reperfusion injury. Hepatology 53:1662-75
Park, Sang Won; Chen, Sean W C; Kim, Mihwa et al. (2010) Protection against acute kidney injury via A(1) adenosine receptor-mediated Akt activation reduces liver injury after liver ischemia and reperfusion in mice. J Pharmacol Exp Ther 333:736-47
Kim, Minjae; Park, Sang Won; Kim, Mihwa et al. (2010) Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 299:F347-58

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