Acute kidney injury (AKI) is a major unresolved clinical problem with an extremely high mortality with a cost of more than 10 billion dollars per year in the United States. Renal ischemia reperfusion (IR) injury is the leading cause of perioperative AKI and frequently complicates major vascular, cardiac and liver surgeries. We previously demonstrated that volatile anesthetics including isoflurane administered after renal ischemia protected against IR injury in part by the synthesis of transforming growth factor-beta 1 (TGF-?1) in proximal tubule cells. However, the downstream cellular signaling events generated by TGF-??1 remain incompletely understood. The overall objective of this proposal is to develop novel therapeutics that protect against ischemic AKI by identifying the signaling events generated by volatile anesthetic-mediated TGF-??1 synthesis. Exciting new preliminary data suggest that the volatile anesthetic agent isoflurane stimulates renal proximal tubular 5'-ectonucleotidase (CD73) to convert extracellular ATP to adenosine which in turn generates the cytoprotective cytokine IL-11 in renal proximal tubular and endothelial cells. This is highly significant as recent studies showed that extracellular ATP released by necrotic cells after IR further promotes inflammation and cell death. Accordingly, our central hypothesis is that volatile anesthetics protect against renal IR injury by inducing renal IL-11 via stimulation of CD73. We will mechanistically link together for the first time several major downstream cytoprotective signaling pathways generated by volatile anesthetics and TGF-??1 (CD73, adenosine and IL-11). As volatile anesthetics are frequently used drugs during the perioperative period, our findings of isoflurane-mediated CD73 modulation and IL-11 generation (a formulation of IL-11 is already clinically available for other applications) have important and novel clinical implications for organ protection beyond the kidney. Our preliminary data lead us to pursue three specific aims that will test our central hypothesis.
Aim #1 : To define the role of CD73 in volatile anesthetic-mediated protection against ischemic AKI.
Aim #2 : To determine the role of IL-11 in volatile anesthetic-mediated protection against ischemic AKI.
Aim #3 : To develop IL-11 based therapy against ischemic AKI. Our translational approach aims to provide conceptual advances regarding how volatile anesthetics confer renal protection by adenosine and IL-11 generation. The major innovations of the proposal include the novelty of the volatile anesthetic-mediated signaling events identified and the significance of the unsolved clinical problem that it addresses. As such, our proposal may identify novel therapeutic targets (e.g., IL-11) and novel therapeutics (polyethylene glycol-conjugated IL-11) to reduce complications of AKI and lead to a radical reduction in mortality and morbidity.

Public Health Relevance

Our translational studies aim to develop novel therapeutic approaches for treating patients with acute kidney injury (AKI), an injury suffered by many patients following surgery on the kidney, liver, heart and aorta. AKI is a major unresolved clinica problem with an extremely high mortality with a cost of more than 10 billion dollars per year in the United States. Our studies suggest that volatile anesthetics, which are used as a component of general anesthesia, activate a cascade of cellular signaling molecules resulting in the activation of 5'-ectonucleotidase (CD73) which scavenges toxic extracellular ATP released from dying cells, and converts it into adenosine which in turn activates receptors that ultimately release a cytoprotective cytokine IL-11. We plan to identify novel therapeutic targets (e.g., IL-11 and novel therapeutics (polyethylene glycol-conjugated IL-11) that could markedly reduce the magnitude of perioperative renal ischemic injury and radically reduce mortality and morbidity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Cole, Alison E
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Columbia University
Schools of Medicine
New York
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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
Kim, Mihwa; Ham, Ahrom; Kim, Katelyn Yu-Mi et al. (2014) The volatile anesthetic isoflurane increases endothelial adenosine generation via microparticle ecto-5'-nucleotidase (CD73) release. PLoS One 9:e99950
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
Fukazawa, Kyota; Lee, H Thomas (2014) Volatile anesthetics and AKI: risks, mechanisms, and a potential therapeutic window. J Am Soc Nephrol 25:884-92
Kim, Mihwa; Ham, Ahrom; Kim, Joo Y et al. (2013) The volatile anesthetic isoflurane induces ecto-5'-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury. Kidney Int 84:90-103
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
Lee, H Thomas; Kim, Joo Yun; Kim, Mihwa et al. (2013) Renalase protects against ischemic AKI. J Am Soc Nephrol 24:445-55
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

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