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

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. Because the inflammasome, interleukin 1 (IL-1), IL-1?/IL-?, and IL-1R are central elements of kidney inflammation and pharmacological IL-1R antagonist (IL-1Ra) 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-1? expression in renal tubular epithelial cells, whereas both IL-1 agonistic molecules (i.e., IL-1? and IL-1?) were devoid of the glomeruli. Human proximal tubular kidney HK-2 cells exposed to high glucose (HG) gradually increase the expression of IL-1? but not IL-1? and induce the expression and deposition of extracellular matrix (ECM) proteins. We further demonstrate that in vitro ectopic addition of recombinant IL-1? 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 protein overexpression and deposition. Accordingly, inhibition of IL-1? cleaving protease calpain, but not caspapse-1, also strongly reduces ECM protein production by HK-2 cells. Collectively, we demonstrate that IL-1? and not IL-1?, 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-1? or IL-1? in order to achieve better blocking of IL-1R signaling.

SUBMITTER: Salti T 

PROVIDER: S-EPMC7358427 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature