AUTHOR=Salti Talal , Khazim Khaled , Haddad Rami , Campisi-Pinto Salvatore , Bar-Sela Gil , Cohen Idan 

TITLE=Glucose Induces IL-1α-Dependent Inflammation and Extracellular Matrix Proteins Expression and Deposition in Renal Tubular Epithelial Cells in Diabetic Kidney Disease

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01270

DOI=10.3389/fimmu.2020.01270

ISSN=1664-3224

ABSTRACT=Diabetes mellitus is linked with metabolic stress that induces cellular damage and can provoke renal inflammation and fibrotic responses that eventually lead to chronic kidney disease. Since the inflammasome-Interleukine-1(IL-1) IL-1α/IL-β-IL-1R are central elements of kidney inflammation and pharmacological IL-1R antagonist was shown to prevent or even reverse diabetic nephropathy (DN) in animal models, we explored the intrinsic expression of IL-1 molecules in kidney tissue of DN patients as regulators of renal inflammation. We used biopsies taken from DN patients and controls and show a high level of IL-1α expression in renal tubular epithelial cells while both IL-1 agonistic molecules (i.e., IL-1α and IL-1β) were devoid of the glomeruli. Human proximal tubular kidney HK-2  cells exposed to high glucose (HG), gradually increase the expression of IL-1α but not IL-1β and induce the expression and deposition of extracellular matrix (ECM) proteins. We further demonstrate that ectopic addition of recombinant IL-1α in low glucose concentration leads to a similar effect as in HG while supplementing excess amounts of IL-1Ra in HG significantly attenuates the ECM proteins overexpression and deposition. Accordingly, Inhibition of IL-1α cleaving protease Calpain, but not Caspapse-1, also strongly reduce ECM protein production by HK-2 cells. Collectively, we demonstrate that IL-1α  released from renal tubular cells is the key inflammatory molecule responsible for the renal inflammation in DN. Our result suggests that the clinical use of IL-1Ra in DN should be promoted over the individual neutralization of IL-1α or IL-1β  in order to achieve better blocking of IL-1R signaling.