snRNAseq of mouse kidney from proximal tubule ACE KO mice

ACE2, a membrane-bound monocarboxypeptidase with high affinity for angiotensin II (AngII), is highly expressed in the renal proximal tubule (PT). Previously, we reported elevated renal AngII levels associated with enhanced hypertension in mice globally lacking ACE2 and a role for soluble ACE2 in hypertension. Using a new mouse model, we now test the hypothesis that the PT of the kidney is a critical site for ACE2 in BP regulation acting via the intra-renal renin angiotensin system. Mice with specific deletion of ACE2 from the PT (PT ACE2 KO) have an exaggerated, initial BP response to AngII infusion, sufficient to cause cardiac hypertrophy. During this early period, reductions in key sodium transporters are observed in PT ACE2 KO mice in contrast to control mice, which instead increase renal ACE2 expression and urinary ACE2 excretion to reduce renal AngII accumulation. Quantitative molecular profiling of sodium transporters reflects impact of ACE2 deletion on homeostasis and offers mechanisms underlying AngII hypertension. Loss of ACE2 from the renal PT is sufficient to cause an exaggerated BP response and concomitant alterations in sodium reabsorption along the entire nephron. These studies reveal a dynamic pattern of intra-renal RAS regulation aimed at mitigating hypertension.