Abstract: TH-PO260

Dendritic Cell Expression of Rictor, but not Raptor, Protects Against AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Rogers, Natasha M., Westmead Institute for Medical Research, Sydney, New South Wales, Australia
  • Dai, Helong, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Fantus, Daniel, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, United States
  • Watson, Alicia, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Thomson, Angus W., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Dendritic cells (DC) are critical to innate immunity in the kidney and orchestrate inflammation fundamental to the pathophysiology of acute kidney injury (AKI). The mechanistic target of rapamycin (mTOR) functions as 2 independent complexes: Raptor and Rictor. The role of mTOR in AKI pathophysiology has been poorly characterized, and the influence of DC-based alterations in mTOR signalling has not been investigated.

Methods

CD11c-specific Raptor-/- or Rictor-/- mice were generated by crossing respective floxed mice with mice expressing CD11c-Cre. Age- and gender-matched DC-mTOR-null mice or littermate controls underwent bilateral renal ischemia-reperfusion injury (IRI), followed by assessment of renal function, histopathology, and biomolecular analysis. Dendritic cells (DC) from WT control, Raptor-/- or Rictor-/- mice were isolated and assessed ex vivo.

Results

CD11c-specific Raptor-/- mice demonstrated no difference in renal function compared to control mice following IRI. However, CD11c-specific Rictor-/- displayed significantly worse renal function and histologic damage at 24 h reperfusion compared to littermate controls. Deterioration in renal function also reflected an aggravated pro-inflammatory cytokine profile (TNFα, IL-1β, IL-6), with kidney-specific increases in CD11b+Ly6G+neutrophil, CD3+ T cell, CD11b+F4/80+macrophage and MHCII+CD11c+DC infiltrates. Increased splenic neutrophil and macrophage infiltrates were also demonstrated in Rictor-/- mice post-IRI. Renal Rictor-/- DC displayed enhanced expression of maturation markers CD40 and CD86, and decreased PD-L1 post-IRI. Ex vivo isolated Rictor-/- DC also demonstrated an enhanced maturation profile compared to WT DC, which was augmented by hypoxia-reoxygenation, and associated with depressed oxidative phosphorylation and increased glycolytic phenotype. Tracking of WT and Rictor-/- DC simultaneously adoptively transferred into B6 mice at the time of renal IRI showed increased numbers of Rictor-/- DC migrating to the injured kidney.

Conclusion

These novel data show that DC-targeted elimination of Rictor promotes IRI, highlighting the regulatory role of both DC and mTOR complex 2 in the pathophysiology of AKI.

Funding

  • Other NIH Support