Date: Sunday, June 3, 2018
Session Time: 2:30pm-4:00pm
Presentation Time: 2:30pm-2:42pm
Location: Room 4C-3
Introduction: The role of the mammalian/mechanistic target of rapamycin (mTOR) in the pathophysiology of renal ischemia-reperfusion injury (IRI) is poorly characterized; furthermore, the influence of dendritic cell (DC)-based alterations in mTOR signaling in IRI has not been investigated.
Methods: We evaluated activation of the mTORC1/2 pathway in sham-operated and post kidney IRI C57BL/6 mice. Ex vivo isolated bone marrow-derived mTORC2 deficient (Rictor-/-) or wild-type (WT) DC underwent hypoxia-reoxygenation and then were analysed by flow cytometry. Adoptive transfer of WT or Rictor-/- DC to C57BL/6 mice followed by unilateral renal IRI was used to assess their in vivo migratory capacity. Age- and gender-matched DC-specific Rictor-/- mice or littermate controls underwent bilateral renal IRI followed by assessment of renal function, renal DC metabolism, histopathology, and bio-molecular and cell infiltration analysis.
Results: Protein expression of phosphorylated S6K that is a downstream of mTORC1 was upregulated, but conversely, phosphorylated AktS473 that is a downstream of mTORC2 was decreased in whole kidney tissue in response to IRI. Rictor-/- DC expressed more CD80/CD86 but less programed death ligand-1 (PDL1) which was enhanced by hypoxia-reoxygenation, and also increased migration to the injured kidney. Following IRI, Rictor-/- DC mice developed higher serum creatinine, more severe histologic damage, and greater pro-inflammatory mRNA transcript profiles of IL-1β, IL-6 and TNF-α compared to littermate controls. After IRI challenge, Rictor-/- DC showed increased TNF-α production, but significantly reduced IL-10 secretion compared to WT DC. Renal Rictor-/- DC were glycolytically biased compared to WT DC under both basal and IRI conditions. A greater influx of both neutrophils and T cells was seen in Rictor-/- DC mice, in addition to CD11c+MHCII+CD11bhiF4/80+ renal DC, that expressed more CD86 but less PDL1.
Conclusions: These novel data suggest that mTORC2 signaling in renal DC negatively regulates acute kidney injury. Thus, DC-targeted elimination of Rictor enhances inflammatory and migratory responses to the injured kidney, highlighting the regulatory roles of both DC and Rictor in the pathophysiology of renal IRI.
CITATION INFORMATION: Dai H., Watson A., Fantus D., Peng L., Thomson A., Rogers N. mTORC2 Deficiency in CD11c+ dendritic Cells Promotes Acute Kidney Injury Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Dai H, Watson A, Fantus D, Peng L, Thomson A, Rogers N. mTORC2 Deficiency in CD11c+ dendritic Cells Promotes Acute Kidney Injury [abstract]. https://atcmeetingabstracts.com/abstract/mtorc2-deficiency-in-cd11c-dendritic-cells-promotes-acute-kidney-injury/. Accessed September 22, 2020.
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