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Kidney Week

Abstract: TH-PO079

Role of Toll Like Receptors in the Pathogenesis of Myeloma Kidney

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Upadhyay, Rohit, Tulane University, New Orleans, Louisiana, United States
  • Ying, Wei-zhong, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Sanders, Paul W., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Jaimes, Edgar A., Memorial Sloan-Kettering Cancer Center, New York, New York, United States
  • Batuman, Vecihi, Tulane University, New Orleans, Louisiana, United States
Background

Free light chains (FLCs) lead to kidney injury (KI) in myeloma patients. We previously demonstrated that inflammatory pathways triggered by endocytosis of FLCs in proximal tubule cells (PTCs) lead to KI. The role of innate immunity mediated by toll-like receptors (TLR) in FLC-associated KI has not been previously investigated. Here we present our initial observations on the role of TLRs in FLC-induced KI in PTCs in-vitro.

Methods

Human kidney PTCs cultures were exposed to κ and λ FLCs. Cell supernatant and pellets were used for ELISA and gene expression studies. Cell proliferation was checked through MTS assay. Data were analyzed using one-way ANOVA with post hoc Tukey test and P values <0.05 were considered significant.

Results

Both κ and λ FLCs induced TNFα secretion and suppressed proliferation of PTCs in a dose- and time-dependent manner. Several innate-immunity (TLRs 2, 3, 4, 6, 9, HMGB1, MYD88, TICAM1), inflammatory (IL6, IL18, IL1B, IL2, TNFα, TGFβ), apoptotic (BCL2, TP53), and KI markers (HAVCR1, ABCB1, LCN2) were assayed. Increased lipocalin 2 (LCN2) and decreased TP53 appeared as the most prominent KI biomarkers for both FLC subtypes. FLCs increased the expression of TLRs 2, 3, 4, 6 and 9, with marked increases in TLR4 gene and in HMGB1 protein levels. Our data show that HMGB1 significantly increases the expression of TLR4 gene in PTCs with or without FLCs exposure. Knock-down of HMGB1 through R, S- Sulforaphane inhibits FLC-induced TLR4 expression suggesting HMGB1 as a likely candidate damage-associated molecular pattern (DAMP) activating TLR4 in FLC exposed PTCs.

Conclusion

PTCs exposed to FLCs release HMGB1, which induces TLR4 expression and downstream inflammation leading to KI. TLRs may be novel diagnostic biomarkers and therapeutic targets for KI in myeloma.

Funding

  • Veterans Affairs Support