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

• Published in: Metabolism, clinical and experimental Vol. 121; p. 154804
• Main Authors: Loretelli, Cristian, Rocchio, Francesca, D'Addio, Francesca, Ben Nasr, Moufida, Castillo-Leon, Eduardo, Dellepiane, Sergio, Vergani, Andrea, Abdelsalam, Ahmed, Assi, Emma, Maestroni, Anna, Usuelli, Vera, Bassi, Roberto, Pastore, Ida, Yang, Jun, El Essawy, Basset, Elased, Khalid M., Fadini, Gian Paolo, Ippolito, Elio, Seelam, Andy Joe, Pezzolesi, Marcus, Corradi, Domenico, Zuccotti, Gian Vincenzo, Gallieni, Maurizio, Allegretti, Marcello, Niewczas, Monika Anna, Fiorina, Paolo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2021
• Subjects: CXCR1; CXCR1/2 blockade; CXCR2; Diabetic kidney disease; IL-8; Podocyte; Type 2 diabetes; ACR; ESRD; Podocyte; Type 2 diabetes; CXCR1/2 blockade; CXCR1; CXCR2; DKD; IL-8; Diabetic kidney disease
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2021.154804

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. 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. 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. 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. •The IL-8-CXCR1/2 axis is overactive in diabetic kidney disease•High glucose stimulates IL-8 secretion in podocytes in vitro•IL-8-CXCR1/2 axis blockade improves renal function in diabetic db/db mice•CXCR1/2 blockade in type 2 diabetes patients may reduce the burden of diabetic kidney disease