Mark D. Okusa, MD, FASN, Division Chief
John C. Buchanan Distinguished Professor of Medicine: Nephrology
UVA Division of Nephrology
PO Box 800133
Charlottesville, VA 22908
EDUCATION AND TRAINING:
- MD, Medical College of Virginia/Virginia Commonwealth University
- Residency, Medical College of Virginia/Virginia Commonwealth University
- Fellowship, Yale School of Medicine
- R01DK105133 (Ultrasound for Non-Invasive Prevention of Acute Kidney Injury)
- NIH/NIDDK 1R01DK123248
- (Neuroimmune Regulation of Acute Kidney Injury)
- R01 DK085259 (Sphingolipids in Acute Kidney Injury and Disease Progression)
- R01 DK123248 (Neuroimmune Regulation of Acute Kidney Injury)
- T32 DK072922 (Kidney Disease and Inflammation)
- Inflammation, fibrosis, progression of kidney disease
Immune Mechanisms of Acute Kidney Injury. We have focused our attention on the immunopathogenesis of acute kidney injury. We have demonstrated the important role that immune cells play in the pathogenesis of AKI. We have described the role of dendritic cells, natural killer T cells, neutrophils, macrophages, and T regulatory cells (Tregs). These studies have demonstrated that early in the course of ischemia-reperfusion injury there is activation of dendritic cells, which leads to glycolipid presentation to natural killer T cells. With our knowledge of the immunopathogenesis of AKI we have been engaged in preclinical studies to characterize the mechanism of action of leading compounds targeted to AKI.
Microenvironment in AKI and AKI to CKD Transition. Our interest in the microenvironment began with our studies with adenosine receptors. Adenosine 2a receptors (A2aR) belong to a class of G-protein coupled receptors comprised of A1, A2a, A2b, A3 receptors. We have studied the role of agonists that bind to A2aR. Administration of an A2aR agonist markedly reduced AKI. We observed that activation of A2aRs in dendritic cells, CD4 cells and T regulatory cells is critically important in contributing to the efficacy of this class of compounds. This compound has important implications not only in systemic administration but also in cell-based therapy. More recently we observed that ATP release channels (Pannexin 1) contribute to AKI through the control of intracellular ATP or through its release into the microenvironment. Whereas much is known about the extracellular role of ATP in activating inflammation, less is know regarding the role of Pannexin 1 channels in controlling intracellular ATP that leads to protection from AKI.
Sphingolipids in Kidney Disease. A second target that we have focused our attention on is the sphingolipid pathway. Sphingosine 1-phosphate is the natural ligand for five G-protein coupled receptors, S1P1-5. Binding to one of these receptors, S1P1, has potent effects to block IRI. Using Cre-Lox technology we have determined that S1P1 in proximal tubule cells, dendritic cells and endothelial cells contribute importantly to the protective effect of S1P1 compounds. Our studies also examine the role of sphingosine kinase 2 in pericytes as a major factor in progression of kidney disease. These studies undergird the development of lead sphingosine kinase 2 inhibitors for attenuation of fibrosis following AKI.
Neuroimmunomodulation in Acute Kidney Injury. We study the inflammatory reflex, a neuro-immune circuit, is critical for immunological homeostasis. The CAP is initiated via activation of the catecholaminergic splenic nerve and release of norepinephrine (NE) and culminates with α7nAChR activation. We have focused on activating this pathway through novel approaches included electrical vagus nerve stimulation, optogenetics and pulse ultrasound. These results suggest that the CAP is important in modulating AKI and that nonpharmacological application of US using parameters within the FDA guidelines may protect kidneys from IRI. Our studies using optogenetics allows precise characterization of the neural circuitry that regulates inflammation.
Photoacoustic Microscopy. In collaboration with Song Hu, PhD. Department of Biomedical Engineering, we have embarked on a high resolution method of measuring peritubular capillary oxygenation that will permit characterization of kidney tubular bioenergetics following acute kidney injury.
We have developed and employed a number of tools that have been instrumental in these studies including: 1) diphtheria-toxin mice, 2) tissue specific and conditional knockout mice, 3) adoptive transfer studies, 4) bone marrow chimeric studies, 5) confocal microscopy, Image Stream analysis, flow cytometry and many others.
PUBLICATION TREE MAP FOR MARK OKUSA
- Li L, L Huang, S-S Sung, PI Lobo, MG Brown, R Gregg, V Engelhard, MD Okusa. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol. 178(9):5899-911, 2007.
- Li, L., L. Huang, S.-S.J. Sung, A.L. Vergis, D.L. Rosin, C. Rose, Jr., P.I. Lobo and MD Okusa. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 74:1526-1537, 2008. PMCID: PMC2652647.
- Li L, L Huang, AL Vergis, H Ye, A Bajwa, V Narayan, RM Strieter, DL Rosin, MD Okusa. IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest. 120(1):331-42, 2010. PMCID: PMC2798679.
- Day Y-J, L Huang, MJ McDuffie, DL Rosin, H Ye, J-F Chen, MA Schwarzschild, JS Fink, J Linden, MD Okusa. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J Clin Invest. 112(6):883-91, 2003. PMCID: PMC193661.
- Li L, L. Huang, H. Ye, S.P. Song, A. Bajwa, S.J. Lee, E.K. Moser, K. Jaworska, G.R. Kinsey, Y.J. Day, J. Linden, P.I. Lobo, D.L. Rosin and MD Okusa Dendritic cells tolerized with adenosine A₂AR agonist attenuate acute kidney injury. J. Clin. Invest. 122:3931–3942, 2012. PMCID:PMC3484444.
- Perry, H.M., L. Huang, R. J. Wilson, H. Sesaki, Z.Yan, D.L. Rosin, D.F. Kashatus, and MD Okusa. Dynamin related protein 1 deficiency promotes recovery from acute kidney injury. J. Am. Soc. Nephrol 29(1):194-206, 2017. PMCID: PMC5748924.
- Jankowski, J., H. M. Perry, L. Huang, D.L. Rosin, B.E. Isakson, K.S. Ravichandran and MD Okusa. ATP Release Through Pannexin1 Channels Mediates Acute Kidney Injury. 29(7):1887-1899, 2018. PMCID: PMC6050932.
- Perry, H.M., N. Görldt, S.S.J. Sung, L. Huang, I.M. Encarnacion, K.Rudnicka, A. Bajwa, S.Tanaka, D.L. Rosin, J. Schrader, MD Okusa. CD73 on perivascular cells modulates the renal microenvironment in kidney interstitial fibrosis. In Press Am J. Physiol. Renal 2019.
- Bajwa, A, L. Huang, H. Ye, J.C. Gigliotti, J. Miller, B. Patel, N. Christian, P.I. Lobo, D.L. Rosin, and MD Okusa. Sphingosine 1-phosphate-3 deficient dendritic cells modulate splenic responses to ischemia-reperfusion injury. J. Am. Soc. Nephrol. 27(4):1076-90, 2016. PMCID: PMC4814185.
- Perry, H.M., L. Huang, H. Ye., C. Liu, S.-S. J. Sung, K.R. Lynch, D. L. Rosin, A. Bajwa, MD Okusa Endothelial sphingosine 1-phosphate receptor 1 mediates protection and recovery from acute kidney injury. J Am Soc Nephrol. J Am Soc Nephrol 27:3383-3393, 2016 PMCID: PMC5084889.
- Bajwa, A., P. L. Huang, E. Kurmaeva, H. Ye, K.R. Dondeti, P. Chroscicki, L.S. Foley, Z.A. Balogun, K.J. Alexander, H. Park, KR Lynch, D.L. Rosin and MD Okusa. Sphingosine kinase 2 deficiency attenuates kidney fibrosis via IFN- J. Am. Soc. Nephrol. 28:1145-1161, 2016. PMCID: PMC5373443.
- Gigliotti, J.C., L. Huang, A. Bajwa, H. Ye, E. Mace, J.A. Hossack, K. Kalantari, T. Inoue, D.L. Rosin and MD Okusa. Ultrasound modulates the splenic neuroimmune axis in attenuating acute kidney injury. J. Am. Soc. Nephrol. J. Am. Soc. Nephrol. 26(10):2470-2481, 2015. PMCID: PMC4587697.
- Inoue, T, C.Abe#, S J. Sung, S. Moscalu, J. Jankowski, L. Huang, H. Ye, D. L. Rosin, PG Guyenet and MD Okusa. Vagus Nerve-Mediated Protection from Kidney Ischemia-Reperfusion Injury through 7nAChR+ Splenocytes. J. Clin. Invest. 2;126(5):1939-1952 2016. #shares co-first authorship with T. Inoue. PMCID: PMC4855936.
- Abe, C.A., T. Inoue#, M.A. Inglis, K.E. Viar, L. Huang, H. Ye, D.L. Rosin, R.L. Stornetta, MD Okusa and PG Guyenet. C1 neurons mediate a stress-induced anti-inflammatory reflex in mice. Nat Neurosci. 20(5):700-707, 2017. #shares co-first authorship with C. Abe. PMCID: PMC5404944.
- Inoue,T., C. Abe, T. Kohro, S. Tanaka, L. Huang, J. Yao, H. Ye, R. L. Stornetta, D. L. Rosin, Y.Wada and MD Okusa. Hes1 dependent vagus nerve stimulation or ultrasound activation of the cholinergic antiinflammatory pathway in acute kidney injury. Kidney Int. 95:563-576, 2019 PMCID: PMC in process.
- Perry, H.M., N. G√∂rldt, S.S.J. Sung, L. Huang, I.M. Encarnacion, K.Rudnicka, A. Bajwa, S.Tanaka, D.L. Rosin, J. Schrader, MD Okusa. CD73 on perivascular cells modulates the renal microenvironment in kidney interstitial fibrosis. In Press Am J. Physiol. Renal 2019.
- Tanaka, S., B. Hammond, D.L. Rosin and MD Okusa. Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway. Bioelectronic Medicine 2019 in press.
- Poudel, N and MD Okusa. Pannexins in acute kidney injury. Nephron, 2019 in press.