Mark D. Okusa, MD, FASN, Division Chief

PRIMARY APPOINTMENT

Mark D. Okusa

John C. Buchanan Distinguished Professor of Medicine: Nephrology

Contact
UVA Division of Nephrology
PO Box 800133
Charlottesville, VA 22908
Telephone: 434-924-2187
Fax: 434-982-5575
Email: mdo7y@virginia.edu

Pub Med
NIH RePORT

EDUCATION AND TRAINING

  • MD, Medical College of Virginia/Virginia Commonwealth University
  • Residency, Medical College of Virginia/Virginia Commonwealth University
  • Fellowship, Yale School of Medicine

FUNDED PROJECTS

  • 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)

RESEARCH AREAS

  • Inflammation, fibrosis, progression of kidney disease

CURRENT LABORATORY MEMBERS

Lab Team Images

  • UVA Nephrology
  • Professor Mark Okusa

    Mark D Okusa, MD

  • group photo of lab members

    Mark D. Okusa Lab Team

  • group photo of lab members

    Mark D. Okusa Lab Team

  • lab member working in the lab

    William Nash, PhD

  • lab member working in the lab

    Shinji Tanaka, MD, PhD

  • lab member working in the lab

    Junlan Yao, PhD

  • lab member working in the lab

    Shuqiu Zheng, MD

  • lab member working in the lab

    Nabin Poudel, PhD

  • Lab member posing with a baseball player cut out

    Mark D. Okusa, MD

  • Lab member working in lab

    Jacqueline Miller

  • group photo of lab members

    Mark D. Okusa Lab Team

  • Lab Group members

    Okusa and Lobo Lab Members

  • Okuso Lab

    Mark D. Okusa Lab Team

  • Okusa Lab member
  • Okusa Lab member
  • UVA Pinn Lab

RESEARCH SUMMARY

Immune Mechanisms of Acute Kidney Injury. We have focused our attention on the immunopathogenesis of acute kidney injury (AKI). 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 the activation of dendritic cells, which leads to glycolipid presentation to natural killer T cells. With our knowledge of the immunopathogenesis of AKIwe 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 ofA2aRs 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 known 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 kinase2 in pericytes as a major factor in the 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 that is critical for immunological homeostasis. The efferent limb of the inflammatory reflex pathway is referred to as the cholinergic anti-inflammatory pathway (CAP), and the CAP is initiated via activation of the catecholaminergic splenic nerve and release of norepinephrine and culminates with activation of α7-nicotinic acetylcholine receptors. We have focused on activating this pathway through novel approaches including electrical vagus nerve stimulation, optogenetics, and pulsed ultrasound. These results suggest that the CAP is important in modulating AKI and that the nonpharmacological application of ultrasound using parameters within the FDA guidelines may protect kidneys from IRI. Our studies using optogenetics allow precise characterization of the neural circuitry that regulates inflammation.

PUBLICATION TREEMAP FOR MARK OKUSA

PUBLICATION TREEMAP FOR MARK OKUSA

114 Urology Nephrology Publications, 23 Physiology Publications, 18 Immunology Publications, 7 Medicine General Internal Publications, 7 Medicine Research Experimental Publications, 3 Critical Care Medicine Publications, 3 Pharmacology Pharmacy Publications, 3 Peripheral Vascular Disease Publications, 3 Transplantation Publications, 2 Cell Biology Publications

 

PUBLICATIONS

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. Poudel, N and MD Okusa. Pannexins in acute kidney injury. Nephron, 2019 in press.