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Kidney Week

Abstract: FR-PO392

Kidney Injury Molecule-1 (KIM-1) Promotes Tertiary Lymphoid Tissue (TLT) Development in the Kidney Through LTaβ/LTβR Signaling

Session Information

  • CKD: Mechanisms - II
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Yang, Min, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Mori, Yutaro, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Murakami, Naoka, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Ichimura, Takaharu, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

TLTs, inducible ectopic lymphoid tissues formed in chronic inflammatory conditions, have been described in various pathologic kidney diseases. However, the links between activation of the inflammation and the triggering cascade of B/T-cell clusters in the kidney are not understood. Here we investigated the role of KIM-1 on tubular epithelial cells (TECs) in affecting the formation of TLTs and modulation of the immune response in kidney injury.

Methods

The immune response associated with TLT formation was investigated using a kidney injury model induced by aristolochic acid (AA) in wild-type (WT) or KIM-1Δ (functional knockout of KIM-1) mouse. Studies in vitro were also done using renal primary TECs isolated from WT or KIM-1Δ mouse kidney, or macrophage cells. Cells were treated with AA and incubated with endothelial cells (ECs, primary mouse kidney endothelial cells and bEND3), followed by measurement of the lymphotoxin pathway, lymphoid chemokines and pro-inflammatory characteristics.

Results

Under AA treatment, WT, but not KIM-1Δ, mice developed multiple TLTs in the kidney, morphologically characterized by high endothelial venules (HEVs) expressing PNAd, germinal centers within B cell follicles and T cells infiltration. These characteristics were associated with higher expression of lymphorganogenic chemokines (CXCL13-CXCR5, CCL21/CCL19-CCR7 axes), adhesion molecules (ICAM1, VCAM1), and IFN-γ in WT mice. Furthermore, in KIM-1Δ mouse IF and qPCR revealed significantly less LTβ expression both on TECs and interstitial inflammatory cells than WT. LTα expression also showed the same trend. However, there was no obvious difference on LTβR expression of ECs. PNAd expression on ECs was induced by incubation with TECs substituted for macrophages or without co-culture conditions in the presence of AA treatment. Compared with WT, KIM-1Δ TECs also displayed reduced expression of LTα, LTβ and induction of HEV marker PNAd following AA stimulation, similar to in vivo.

Conclusion

KIM-1 plays a critical role in initiation of the inflammatory response by activating HEV through LTαβ/LTβR signaling, providing inflammatory milieu to enhance immune cell infiltration. These findings provide a new insight that TECs modulate immune reaction in kidney injury and can be a therapeutic target for inflammatory renal diseases.

Funding

  • NIDDK Support