title: Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice.
abstract: Angiotensin-converting enzyme 2 (ACE2) gene therapy aimed at counteracting pancreatic ACE2 depletion improves glucose regulation in two diabetic mouse models: db/db mice and angiotensin II-infused mice. A disintegrin and metalloproteinase 17 (ADAM17) can cause shedding of ACE2 from the cell membrane. The aim of our studies was to determine whether ADAM17 depletes ACE2 levels in pancreatic islets and β-cells. Dynamics of ADAM17-mediated ACE2 shedding were investigated in 832/13 insulinoma cells. Within a wide range of ACE2 expression levels, including the level observed in mouse pancreatic islets, overexpression of ADAM17 increases shed ACE2 and decreases cellular ACE2 levels. We provide a mathematical description of shed and cellular ACE2 activities as a function of the ADAM17 activity. The effect of ADAM17 on the cellular ACE2 content was relatively modest with an absolute control strength value less than 0.25 and approaching 0 at low ADAM17 activities. Although we found that ADAM17 and ACE2 are both expressed in pancreatic islets, the β-cell is not the major cell type expressing ACE2 in islets. During diabetes progression in 8-, 12-, and 15-week-old db/db mice, ACE2 mRNA and ACE2 activity levels in pancreatic islets were not decreased over time nor significantly decreased compared with nondiabetic db/m mice. Levels of ADAM17 mRNA and ADAM17 activity were also not significantly changed. Inhibiting basal ADAM17 activity in mouse islets failed to affect ACE2 levels. We conclude that whereas ADAM17 has the ability to shed ACE2, ADAM17 does not deplete ACE2 from pancreatic islets in diabetic db/db mice.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics (K.B.P., H.C., L.K.R., E.L.) and Department of Physiology, Comprehensive Alcohol Research Center (C.P.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Kim Brint
authors.initials: KB
authors.lastname: Pedersen
authors.affiliation: Department of Pharmacology and Experimental Therapeutics (K.B.P., H.C., L.K.R., E.L.) and Department of Physiology, Comprehensive Alcohol Research Center (C.P.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Harshita
authors.initials: H
authors.lastname: Chodavarapu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics (K.B.P., H.C., L.K.R., E.L.) and Department of Physiology, Comprehensive Alcohol Research Center (C.P.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Constance
authors.initials: C
authors.lastname: Porretta
authors.affiliation: Department of Pharmacology and Experimental Therapeutics (K.B.P., H.C., L.K.R., E.L.) and Department of Physiology, Comprehensive Alcohol Research Center (C.P.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Leonie K
authors.initials: LK
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology and Experimental Therapeutics (K.B.P., H.C., L.K.R., E.L.) and Department of Physiology, Comprehensive Alcohol Research Center (C.P.), Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats
chemical_list: D012333:RNA, Messenger; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat