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Abstract: TH-PO891

TWEAK-Fn14 Signalling in Mesangial Cells Drives Intrarenal Inflammation During CKD Progression

Session Information

Category: CKD (Non-Dialysis)

  • 2201 CKD (Non-Dialysis): Epidemiology‚ Risk Factors‚ and Prevention

Authors

  • Seth, Asha, AstraZeneca PLC, Cambridge, Cambridgeshire, United Kingdom
  • Musial, Barbara, AstraZeneca PLC, Cambridge, Cambridgeshire, United Kingdom
  • Haschler, Timo Nicolas, AstraZeneca PLC, Cambridge, Cambridgeshire, United Kingdom
  • Wang, Hong, AstraZeneca PLC, Cambridge, Cambridgeshire, United Kingdom
  • Laerkegaard Hansen, Pernille B., AstraZeneca, Gothenburg, Sweden
Background

It is increasingly recognised that inflammation evokes renal injury and promotes chronic kidney disease (CKD) progression. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a pleiotropic cytokine, which binds to fibroblast growth factor-inducible-14 (Fn14). TWEAK-Fn14 signalling has been linked with pathogenic processes in the kidney that may contribute to the progression of CKD. However, whether this pathway is a key driver of human disease has yet to be established.

Methods

To further explore the relevance of TWEAK-Fn14 signalling in CKD we have used human transcriptomic data sets and IHC to interrogate the expression of both ligand and receptor in kidney disease. We have then used human primary mesangial cells to identify regulators of Fn14 expression and explore the mechanisms regulated by the TWEAK-Fn14 pathway in renal cells. Finally, we have used a neutralising TWEAK antibody in vitro and in vivo to explore the therapeutic potential of intervening in this pathway.

Results

Fn14 expression was found to be upregulated in biopsies collected from CKD patients as compared to healthy living donors and was also highly correlated with increased kidney damage. IHC showed in patients with DKD, or in pre-clinical models of CKD, Fn14 was localised to the glomerulus, in a pattern consistent with mesangial expression, and in tubule cells. In primary human mesangial cells, PDGF-BB treatment increased cell surface Fn14 expression 9.6-fold. TWEAK application to mesangial cells dose-dependently induced increases in cell proliferation and the release of IL-8 and MCP-1. These effects were blocked by treatment with a neutralising TWEAK antibody. We further tested the beneficial effects of TWEAK neutralization in a murine model of rapid progressive glomerulonephritis induced by administration of nephrotoxic serum. We found that anti-TWEAK treatment significantly decreased MCP-1 transcript expression in the kidney and reduced the level of urinary MCP-1 indicating a reduction in intrarenal inflammation.

Conclusion

Fn14 is regulated in human CKD and is highly correlated with disease severity in CKD. In human primary mesangial cells Fn14 activation leads chemokines release. In vivo, TWEAK neutralisation translates into a decrease in the level of kidney MCP-1.

Funding

  • Commercial Support