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Kidney Week

Abstract: FR-OR15

Kidney Injury Molecule-1 (KIM-1) Shapes the Kidney Immune Microenvironment via Lymphotoxin Beta Receptor (LTbR) Signaling

Session Information

  • AKI Research: Mechanisms
    November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
    Abstract Time: 05:06 PM - 05:15 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Murakami, Naoka, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Kawashima, Shun, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Mori, Yutaro, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Yu, Samuel Mon-Wei, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Ichimura, Takaharu, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues which are found in chronic inflammatory conditions and in various pathologic kidney diseases. However, the mechanisms of TLT formation in kidney and its implication in acute kidney injury are poorly understood.

Methods

In an aristolochic acid (AA)-induced kidney injury mouse model, we analyzed the resultant immune microenvironment in KIM-1 wild type (WT) and KIM-1 mutant (delta mucin, functional knockout of KIM-1) animals. Gene expression was examined in kidneys harvested on day 14 after AA treatment (5 mg/kg, intraperitoneal injection, once). Primary mouse kidney tubular epithelial cells (TEC), derived from WT and KIM-1 mutant kidneys were treated with AA and assessed cytokine production. In addition, immune-related gene expression profiles were examined using human kidney biopsy samples.

Results

AA treatment induced more prominent TLTs in kidney interstitium in KIM-1 WT animals, associated with higher levels of lymphotoxin beta (LTb) and its receptor (LTbR) expression in the kidneys when compared to results in KIM-1 mutant animals, suggesting that the expression of KIM-1 plays a role in lymphocyte trafficking. Gene expression of chemokine ligand/receptor pairs such as CXCL13/CXCR5, CCL21/CCR7, were also higher in KIM-1 WT compared to KIM-1delta-mucin mutants. Primary tubule epithelial cells (TECs) co-cultured with endothelial cells revealed that AA treatment in vitro induced higher CXCL13 and CCL21 secretion in cells derived from WT animals as compared to TECs isolated from KIM-1Dmucin animals, and greater endothelial activation evident by increased PNAd. Human kidney biopsy samples from patients with drug-induced AKI confirmed expression of LTb, CXCL13 and CCL21, suggesting the relevance of these molecules in human AKI.

Conclusion

KIM-1 expression plays a crucial role on lymphocyte trafficking via inducing expression of LTb/LTbR and chemokines in kidneys. Our data provide novel information to suggest epithelial-endothelial-immune crosstalk and may lead to identification of novel therapeutic targets.

Funding

  • NIDDK Support