Inhibition of interleukin-33 to reduce glomerular endothelial inflammation in diabetic kidney disease
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
INTRODUCTION: Inflammation is a significant contributor to cardiorenal morbidity and mortality in diabetic kidney disease (DKD). The pathophysiological mechanisms linking systemic, subacute inflammation and local, kidney injury-initiated immune maladaptation is partially understood. METHODS: Here, we explored the expression of proinflammatory cytokines in patients with DKD; investigated mouse models of type 1 and type 2 diabetes (T2D); evaluated glomerular signaling in vitro; performed post hoc analyses of systemic and urinary markers of inflammation; and initiated a phase 2b clinical study (FRONTIER-1; NCT04170543). RESULTS: Transcriptomic profiling of kidney biopsies from patients with DKD revealed significant glomerular upregulation of interleukin-33 (IL-33). Inhibition of IL-33 signaling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model (T2D/DKD). On a cellular level, inhibiting IL-33 improved glomerular endothelial health by decreasing cellular inflammation and reducing release of proinflammatory cytokines. Therefore, FRONTIER-1 was designed to test the safety and efficacy of the IL-33-targeted monoclonal antibody tozorakimab in patients with DKD. So far, 578 patients are enrolled in FRONTIER-1. The baseline inflammation status of participants (N > 146) was assessed in blood and urine. Comparison to independent reference cohorts (N > 200) validated the distribution of urinary tumor necrosis factor receptor 1 (TNFR1) and C-C motif chemokine ligand 2 (CCL2). Treatment with dapagliflozin for 6 weeks did not alter these biomarkers significantly. CONCLUSION: We show that blocking the IL-33 pathway may mitigate glomerular endothelial inflammation in DKD. The findings from the FRONTIER-1 study will provide valuable insights into the therapeutic potential of IL-33 inhibition in DKD.
Date Issued
2024-06
Date Acceptance
2024-03-11
Citation
Kidney International Reports, 2024, 9 (6), pp.1876-1891
ISSN
2468-0249
Publisher
Elsevier
Start Page
1876
End Page
1891
Journal / Book Title
Kidney International Reports
Volume
9
Issue
6
Copyright Statement
© 2024 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38899206
Subjects
biomarker
diabetic kidney disease
IL-33
inflammation
phase 2b
tozorakimab
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-03-18