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ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis.

ABSTRACT: ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in inhibited EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl₄ intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development. Furthermore, we show that while ablation of ADAM17 resulted in decreased shedding of TNF RI, ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.

SUBMITTER: Zbodakova O

PROVIDER: S-EPMC8169909 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ADAM10 and γ-secretase regulate sensory regeneration in the avian vestibular organs.

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2016-10-27 | GSE77867 | GEO

ADAM10 and ADAM17, Major Regulators of Chronic Kidney Disease Induced Atherosclerosis?

Project description:Chronic kidney disease (CKD) is a major health problem, affecting millions of people worldwide, in particular hypertensive and diabetic patients. CKD patients suffer from significantly increased cardiovascular disease (CVD) morbidity and mortality, mainly due to accelerated atherosclerosis development. Indeed, CKD not only affects the kidneys, in which injury and maladaptive repair processes lead to local inflammation and fibrosis, but also causes systemic inflammation and altered mineral bone metabolism leading to vascular dysfunction, calcification, and thus, accelerated atherosclerosis. Although CKD and CVD individually have been extensively studied, relatively little research has studied the link between both diseases. This narrative review focuses on the role of a disintegrin and metalloproteases (ADAM) 10 and ADAM17 in CKD and CVD and will for the first time shed light on their role in CKD-induced CVD. By cleaving cell surface molecules, these enzymes regulate not only cellular sensitivity to their micro-environment (in case of receptor cleavage), but also release soluble ectodomains that can exert agonistic or antagonistic functions, both locally and systemically. Although the cell-specific roles of ADAM10 and ADAM17 in CVD, and to a lesser extent in CKD, have been explored, their impact on CKD-induced CVD is likely, yet remains to be elucidated.

| S-EPMC10139114 | biostudies-literature

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