541-P: The Il-8-CXCR1/2 Axis and Its Targeting in Diabetic Kidney Disease

Introduction: Recent studies suggested a major involvement of the inflammation process in the onset and maintenance of diabetic kidney disease (DKD). We aimed to evaluate the role of the IL-8-CXCR1/2 pathway in DKD.

Material and Methods: Human studies: We measured the urinary IL-8 levels from a cohort of 1182 patients affected by type 2 diabetes (T2D) using Luminex and quantified IL-8 protein/mRNA expression in kidney samples by immunohistochemistry, immunofluorescence and RT-PCR. Murine in vivo studies: The expression of KC (a murine homologue of IL-8) was quantified during the progression of DKD while the effect of CXCR1/2 blockade was analyzed in diabetic Lep^db/db mice. In vitro studies: We mechanistically determined the impact of the IL-8-CXCR1/2 pathway in vitro in an immortalized cell line of human podocytes.

Results: (i) Human studies: IL-8 urinary levels are increased in T2D patients with DKD. In addition, we found that those with microalbuminuria showed high urinary IL-8 levels which are associated with a higher Glomerular Filtration Rate (GFR) decline, a significant increase of the Albumin/Creatine Ratio (ACR) and development of worst renal outcomes. Patients affected by T2D and DKD have higher IL-8 glomerular expression compared to controls. CXCR1/2 are mainly localized at glomerular level and expressed by podocytes while IL-8 is localized in CD31⁺ endothelial cells. (ii) Murine studies: KC blockade reduces albuminuria and renal damage in Lep^db/db mice. (iii) In vitro studies: Podocytes express high levels of CXCR1/2. Treatments with the recombinant IL-8 induce DNA damage in podocytes while CXCR1/2 blockade prevent it.

Conclusion: IL-8-CXCR1/2 pathway may have a role in DKD onset by inducing a podocyte-mediated damage and its blockade may represent an add-on therapy to current therapeutic strategies.