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Article

Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

1
Department of Pediatrics, The University of Tennessee Health Science Center, Memphis, TN 38103, USA
2
Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
3
Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
4
Department of Surgery, Surgical Sciences Division, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
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Department of Systems and Computational Biology, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
6
Division of Transplant Surgery, University of Maryland Medical Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
7
Department of Microbiology, Immunology, and Biochemistry; College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Joan Roselló-Catafau
Int. J. Mol. Sci. 2021, 22(10), 5386; https://doi.org/10.3390/ijms22105386
Received: 19 April 2021 / Revised: 13 May 2021 / Accepted: 17 May 2021 / Published: 20 May 2021
(This article belongs to the Special Issue Pathobiology of Acute Kidney Injury)
Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury. View Full-Text
Keywords: dendritic cell; rapamycin; mitochondria; acute kidney injury; ischemic reperfusion injury dendritic cell; rapamycin; mitochondria; acute kidney injury; ischemic reperfusion injury
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MDPI and ACS Style

Namwanje, M.; Bisunke, B.; Rousselle, T.V.; Lamanilao, G.G.; Sunder, V.S.; Patterson, E.C.; Kuscu, C.; Kuscu, C.; Maluf, D.; Kiran, M.; Mas, V.; Eason, J.D.; Bajwa, A. Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury. Int. J. Mol. Sci. 2021, 22, 5386. https://doi.org/10.3390/ijms22105386

AMA Style

Namwanje M, Bisunke B, Rousselle TV, Lamanilao GG, Sunder VS, Patterson EC, Kuscu C, Kuscu C, Maluf D, Kiran M, Mas V, Eason JD, Bajwa A. Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury. International Journal of Molecular Sciences. 2021; 22(10):5386. https://doi.org/10.3390/ijms22105386

Chicago/Turabian Style

Namwanje, Maria, Bijay Bisunke, Thomas V. Rousselle, Gene G. Lamanilao, Venkatadri S. Sunder, Elizabeth C. Patterson, Canan Kuscu, Cem Kuscu, Daniel Maluf, Manjari Kiran, Valeria Mas, James D. Eason, and Amandeep Bajwa. 2021. "Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury" International Journal of Molecular Sciences 22, no. 10: 5386. https://doi.org/10.3390/ijms22105386

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