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The therapeutic potential of an allosteric non-competitive CXCR1/2 antagonist for diabetic nephropathy

Chiara Grasselli1, Silvia Bombelli1, Vittoria D'Esposito2

  • 1Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Diabetes/Metabolism Research and Reviews
|July 20, 2023
PubMed
Abstract

Insights

Ladarixin, a CXCR1/2 antagonist, protected kidney cells from high glucose damage in vitro. This suggests CXCR1/2 antagonists may treat diabetic nephropathy by reducing inflammation.

Area of Science:

  • Nephrology
  • Immunology
  • Endocrinology

Background:

  • Diabetic nephropathy involves inflammation, with the IL-8/CXCR1/2 pathway crucial for kidney damage in type 1 diabetes.
  • Understanding cellular responses to hyperglycemia is key to developing targeted therapies.

Purpose of the Study:

  • To investigate the therapeutic potential of Ladarixin, a CXCR1/2 antagonist, against high glucose-induced injury in renal cells.
  • To explore the role of the IL-8/CXCR1/2 axis in diabetic nephropathy using human renal stem cells (RSCs).

Main Methods:

  • Human RSCs were cultured as nephrospheres to model kidney development and disease.
  • Hyperglycemia's effects on IL-8 signaling, podocytes, and epithelial cells were examined.
  • Ladarixin's impact on high glucose-mediated cellular damage and inflammation was assessed.

Main Results:

  • High glucose impaired RSC self-renewal and induced DNA damage in podocytes, increasing IL-8 expression and secretion.
  • Supernatants from high glucose-treated cells differentially activated leukocyte-mediated pro-inflammatory cytokine release.
  • Ladarixin treatment prevented high glucose-induced podocyte injury and modulated inflammatory responses.

Conclusions:

  • Ladarixin effectively protected renal cells from high glucose damage, highlighting its therapeutic potential.
  • Modulation of the IL-8/CXCR1/2 axis by antagonists like Ladarixin offers a promising strategy for treating diabetic nephropathy.
Keywords:
CXCR1/2IL-8Ladarixindiabetic nephropathyrenal stem celltype 1 diabetes

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