Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes

Abstract

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.

Endothelial ADAM17 Expression in the Progression of Kidney Injury in an Obese Mouse Model of Pre-Diabetes

“…Probably this mild protection against glucose intolerance can be explained by the modulation of Sodium-Glucose Cotransporter-2 (SGLT2) after Adam17 deletion. As we have recently described [ 31 ], Adam17 deletion may decrease SGLT2 activity, preventing HFD animals from proximal tubular glucose reabsorption by favouring its urinary excretion. HFD-mice with Adam17 deleted in endothelial cells presented decreased SGLT2 expression.…”

Immunomodulatory role of metalloproteinase ADAM17 in tumor development

“…The expression of ADAM17 in mouse articular cartilage is positively correlated with the development of arthritis, and its deletion attenuates articular cartilage degeneration (8). Moreover, ADAM17 is associated with glomerular inflammation and fibrosis (9). In diabetic mice, ADAM17 deletion in the proximal tubules improves glucose tolerance, prevents podocyte loss, and inhibits the accumulation of glomerular macrophages and collagen (9).…”

“…Moreover, ADAM17 is associated with glomerular inflammation and fibrosis (9). In diabetic mice, ADAM17 deletion in the proximal tubules improves glucose tolerance, prevents podocyte loss, and inhibits the accumulation of glomerular macrophages and collagen (9). More importantly, ADAM17 is contributory to the occurrence and development of cancers, including lung carcinoma (10), ovarian carcinoma (11), breast carcinoma (12)(13)(14), gastric carcinoma (15), and cervical carcinoma (16).…”

Underestimated Prediabetic Biomarkers: Are We Blind to Their Strategy?

“…It was observed a reduction in Gal3 and an improvement of beta-cell dysfunction (22). Study of renal function and prediabetic mouse model observed higher levels of Gal3 in the proximal tubules and glomeruli of HFD mice and attenuated by Adam17 depletion (45). Diabetic mouse model presented higher levels of Gal3 in liver and kidney and Gal3 was correlated with oxidative stress, specifically with AGE products and 3NT (22).…”