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Shedding of ACE2 by mature form of ADAM17 is mediated by angiotensin type 1 receptor (1108.14)

ADAM17 (a disintegrin and metalloprotease) is associated with shedding of ACE2 in diabetic rodent models with overactive Renin‐Angiotensin System. To test the role of ADAM17 in pancreatic ACE2 shedding, C57Bl/6J mice (n=5/group) were fed high fat diet (HFD) for 16 weeks. HFD fed mice showed hyperglycemia (HFD: 150 ±10.7 vs. Control: 103 ±3.6 mg/dl P<0.05) and glucose intolerance (HFD: 43438 ±2803 vs. Control: 35903 ±2075 AU P<0.05). Western blot and Quantitative RT‐PCR showed 2 fold increase in both pancreatic ADAM17 protein and mRNA expression (p<0.05) in HFD mice. This was associated with a 1.5 fold reduction (p<0.05) in pancreatic ACE2 protein and 1.5 fold increase (p<0.05) in mRNA expression in HFD mice. To directly implicate the role of Angiotensin (Ang) II type 1 receptor (AT1R) in ADAM17 expression, an immortalized human pancreatic beta cell line (β‐lox 5) was used. Treatment with 500 nM Ang II resulted in 2 fold increase (p<0.05) in ADAM17 protein expression which was attenuated by losartan (AT1R blocker). Further, transfection of β‐lox 5 cells with hACE2/pcDNA3.1 followed by treatment with an ADAM17 overexpressing adenovirus resulted in 2 fold increase in the pro form (p<0.05) but not the mature form of ADAM17 protein expression and no change in hACE2 expression. In conclusion, our results demonstrate that AT1R‐mediated increase in the mature form of ADAM17 is responsible for the shedding of pancreatic ACE2.