Aims/hypothesis:Inflammation has a major role in diabetic kidney disease. We thus investigated the roleof 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 patientswith 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 uri-nary IL-8 levels found in the patients with the largest decline in glomerularfiltration rate, with an increasedalbumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increasedin patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured humanimmortalized podocytesin vitro. Finally, in diabetic db/db mice and in podocytesin vitro, CXCR1/2 blockade mit-igated 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 inducingpodocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease
The IL-8-CXCR1/2 axis contributes to diabetic kidney disease / C. Loretelli, F. Rocchio, F. D'Addio, M.B. Nasr, E. Castillo-Leon, S. Dellepiane, A. Vergani, A. Abdelsalam, E. Assi, A. Maestroni, V. Usuelli, R. Bassi, I. Pastore, J. Yang, B. El Essawy, K.M. Elased, G.P. Fadini, E. Ippolito, A.J. Seelam, M. Pezzolesi, D. Corradi, G.V. Zuccotti, M. Gallieni, M. Allegretti, M.A. Niewczas, P. Fiorina. - In: METABOLISM, CLINICAL AND EXPERIMENTAL. - ISSN 0026-0495. - 121(2021 Aug), pp. 154804.1-154804.8. [10.1016/j.metabol.2021.154804]
The IL-8-CXCR1/2 axis contributes to diabetic kidney disease
C. Loretelli;F. Rocchio;F. D'Addio;M.B. Nasr;A. Abdelsalam;E. Assi;A. Maestroni;V. Usuelli;I. Pastore;E. Ippolito;A.J. Seelam;G.V. Zuccotti;M. Gallieni;P. Fiorina
2021
Abstract
Aims/hypothesis:Inflammation has a major role in diabetic kidney disease. We thus investigated the roleof 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 patientswith 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 uri-nary IL-8 levels found in the patients with the largest decline in glomerularfiltration rate, with an increasedalbumin/creatine ratio and the worst renal outcome. Moreover, glomerular IL-8 renal expression was increasedin patients with T2D, as compared to controls. High glucose elicits abundant IL-8 secretion in cultured humanimmortalized podocytesin vitro. Finally, in diabetic db/db mice and in podocytesin vitro, CXCR1/2 blockade mit-igated 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 inducingpodocyte damage. Indeed, targeting the IL-8-CXCR1/2 axis may reduce the burden of diabetic kidney disease
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