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Kidney Week

Abstract: SA-PO604

Renal Tubular Epithelial Cell Proliferation Inhibition by C-Reactive Protein and Myeloid Derived Suppressor Cells

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Jimenez, Rachel, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Szalai, Alexander J., The University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Re-establishment of renal function after acute kidney injury (AKI) largely depends on the recovery of injured renal tubular epithelial cells (RTEC). However, the inflammatory response that accompanies AKI complicates RTEC recuperation. In a series of studies, we showed that C-reactive protein (CRP), a well-known biomarker of inflammation, plays a causal role in AKI i.e. human CRP transgenic mice (CRPtg) subjected to renal ischemia-reperfusion have more severe AKI compared to CRP knockout mice. Notably, for CRPtg the exacerbation of AKI is accompanied by increased renal infiltration by myeloid derived suppressor cells (MDSC), and depletion of human CRP blunts both MDSC infiltration and renal injury. In the present study we explored the CRP → MDSC → RTEC axis.

Methods

To determine the direct impact of human CRP on MDSC functions and RTEC health, and to establish whether MDSCs can suppress RTEC proliferation, primary mouse RTECs were isolated and mouse MDSCs were generated from bone marrow (BM-MDSC) and studied in vitro using microscopy, flow cytometry, and co-culture assays.

Results

We first confirmed that BM-MDSCs (CD11b+CD11c-F4/80-Ly6C+Ly6G+ cells with an immature nuclear morphology) effectively suppressed the proliferation of CD3ε/CD28-stimulated CD4+ T cells and that this BM-MDSC suppressive action is enhanced by human CRP. When human CRP was added to freshly isolated bone marrow, human CRP increased the proportion of BM-MDSCs ultimately generated and also increased the proportion of BM-MDSCs entering S phase. Co-cultures with BM-MDSCs in transwells inhibited the cell cycling of primary RTEC monolayers.

Conclusion

Our results show that human CRP promotes the generation of MDSCs from bone marrow precursors and enhances their ability to suppress target-cells. Our initial evidence suggests BM-MDSCs suppress primary RTEC cell cycling in a contact-independent manner. These new in vitro data align with our earlier observation that AKI is worsened in CRPtg. We hypothesize that in CRPtg with AKI, human CRP enhances the noxious effects of renal infiltrating MDSCs, thereby promoting inhibition of RTEC and delaying their recovery. Ongoing work investigates whether human CRP enhances the MDSC-mediated suppression of RTEC proliferation and whether this effect requires MDSC expression of CRP receptor(s).

Funding

  • NIDDK Support