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

Cristian Loretelli, Francesca Rocchio, Francesca D'Addio, Moufida Ben Nasr, Eduardo Castillo-Leon, Sergio Dellepiane, Andrea Vergani, Ahmed Abdelsalam, Emma Assi, Anna Maestroni, Vera Usuelli, Roberto Bassi, Ida Pastore, Jun Yang, Basset El Essawy, Khalid M. Elased, Gian Paolo Fadini, Elio Ippolito, Andy Joe Seelam, Marcus PezzolesiDomenico Corradi, Gian Vincenzo Zuccotti, Maurizio Gallieni, Marcello Allegretti, Monika Anna Niewczas, Paolo Fiorina

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish
Article number154804
JournalMetabolism: Clinical and Experimental
Volume121
DOIs
StatePublished - Aug 2021
Externally publishedYes

Keywords

  • CXCR1
  • CXCR1/2 blockade
  • CXCR2
  • Diabetic kidney disease
  • IL-8
  • Podocyte
  • Type 2 diabetes

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