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Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease.
- Source :
-
Kidney international reports [Kidney Int Rep] 2024 Mar 18; Vol. 9 (6), pp. 1876-1891. Date of Electronic Publication: 2024 Mar 18 (Print Publication: 2024). - Publication Year :
- 2024
-
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.<br />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).<br />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.<br />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.<br /> (© 2024 International Society of Nephrology. Published by Elsevier Inc.)
Details
- Language :
- English
- ISSN :
- 2468-0249
- Volume :
- 9
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Kidney international reports
- Publication Type :
- Academic Journal
- Accession number :
- 38899206
- Full Text :
- https://doi.org/10.1016/j.ekir.2024.03.009