The IL-8-CXCR1/2 axis contributes to diabetic kidney disease

Metabolism. 2021 Aug;121:154804. doi: 10.1016/j.metabol.2021.154804. Epub 2021 Jun 10.

Abstract

Aims/hypothesis: Inflammation has a major role in diabetic kidney disease. We thus investigated the role of the IL-8-CXCR1/2 axis in favoring kidney damage in diabetes.

Methods: Urinary IL-8 levels were measured in 1247 patients of the Joslin Kidney Study in type 2 diabetes (T2D). The expression of IL-8 and of its membrane receptors CXCR1/CXCR2 was quantified in kidney tissues in patients with T2D and in controls. The effect of CXCR1/2 blockade on diabetic kidney disease was evaluated in db/db mice.

Results: IL-8 urinary levels were increased in patients with T2D and diabetic kidney disease, with the highest urinary IL-8 levels found in the patients with the largest decline in glomerular filtration rate, with an increased albumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increased in patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured human immortalized podocytes in vitro. Finally, in diabetic db/db mice and in podocytes in vitro, CXCR1/2 blockade mitigated albuminuria, reduced mesangial expansion, decreased podocyte apoptosis and reduced DNA damage.

Conclusions/interpretation: The IL-8- CXCR1/2 axis may have a role in diabetic kidney disease by inducing podocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease.

Keywords: CXCR1; CXCR1/2 blockade; CXCR2; Diabetic kidney disease; IL-8; Podocyte; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Cohort Studies
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Humans
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Interleukin-8 / physiology*
  • Italy
  • Kidney / metabolism
  • Kidney / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Podocytes / metabolism
  • Podocytes / pathology
  • Receptors, CXCR / physiology*
  • Receptors, Interleukin-8A / genetics
  • Receptors, Interleukin-8A / metabolism
  • Receptors, Interleukin-8B / genetics
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction / physiology

Substances

  • Interleukin-8
  • Receptors, CXCR
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B