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We employed a mouse model of PT-specific ACE2 deletion (PT ACE2\u2013KO) to demonstrate that the renal PT is a critical site for ACE2 regulation of blood pressure (BP) via modulation of the intrarenal renin-angiotensin system (RAS). While deletion of ACE2 from the PT had a minimal effect on baseline physiology, PT ACE2\u2013KO mice were more susceptible to AngII hypertension than control mice. At day 5 of AngII infusion, the enhanced BP response was associated with cardiac hypertrophy, increased renal AngII levels, failure to suppress epithelial sodium channel (ENaC) \u03b3 cleavage, and increased sodium pump activity in PT ACE2\u2013KO mice. Control mice instead increased renal ACE2 expression to reduce renal AngII accumulation and suppress intrarenal RAS activation, which offered protection from hypertension and complications. 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