Deletion of intratubular renin-angiotensin system selectively in the proximal tubules alters renal cortical and medullary blood flows in angiotensin II-induced hypertensive mice

Intratubular renin-angiotensin system (RAS) in the kidney is well recognized to play an important role in the regulation of proximal tubule sodium reabsorption, basal blood pressure homeostasis, as well as in the development of angiotensin II (Ang II)-induced hypertension. However, little is known whether intratubular RAS plays a physiological role in the regulation of renal cortical and medullary blood flows under physiological conditions and during the development of Ang II-induced hypertension. In the present study, we hypothesized that angiotensinogen (AGT), Ang II AT1a receptor, and its downstream target Na+/H+ exchanger 3 (NHE3) in the proximal tubules are required to physiologically regulate renal cortical and medullary blood prefusion in mice and in Ang II-induced hypertension. To test the hypothesis, we generated mutant mouse models with proximal tubule-specific deletion of AGT (PT-Agt-/-) or AT1a receptor and NHE3 (PT-Agtr1a-/-/PT-Nhe3-/-), respectively. Male wild-type (WT), PT-Agt-/-, and PT-Agtr1a-/-/PT-Nhe3-/- mice (n=5 per group) were treated without (Control) or with Ang II infusion via an osmotic minipump for 2 weeks (0.5 mg/kg/day, i.p.). Systolic blood pressure was determined using the tail-cuff method, whereas renal cortical blood flow (CBF) and medullary blood flow (MBF) were measured using a laser-doppler flowmeter (PeriFlux 6000, PERIMED) under anesthesia conditions. Compared with WT controls, basal systolic blood pressure was ~10 ± 3 mmHg lower in PT-Agt-/- mice (P< 0.01), and ~18 ± 3 mmHg lower in PT-Agtr1a-/-/PT-Nhe3-/- double knockout mice (P< 0.01), respectively. Ang II significantly increased systolic blood pressure in WT mice by ~43 ± 5 mmHg (P< 0.01), PT-Agt-/- mice by 38 ± 3 mmHg (P< 0.01), and in PT-Agtr1a-/-/PT-Nhe3-/- mice by 20 ± 3 mmHg (P< 0.01), respectively. In WT mice, basal CBF was 330.2 ± 8.2 PFU (perfusion unit), which was significantly decreased to 236.5 ± 7.2 PFU in response to 2-week Ang II infusion (P< 0.01). Basal MBF was 55.8 ± 3.0 PFU, which was also decreased significantly to 45.4 ± 3.9 PFU in response to Ang II infusion (P< 0.05). In PT-Agt-/- mice, basal CBF (391.9 ± 10.2 PFU) and MBF (97.2 ± 4.4 PFU) were significantly higher than those of WT mice (P< 0.01). In response to Ang II infusion, CBF was decreased to 322.9 ± 9.6 PFU (P< 0.05), whereas MBF was decreased to 68.2 ± 3.4 PFU (P< 0.05), respectively. In PT-Agtr1a-/-/PT-Nhe3-/- double knockout mice, basal CBF was similar to that of PT-Agt-/- mice, whereas Ang II infusion also decreased CBF to a similar extent to that of PT-Agt-/- mice (P< 0.05). However, Ang II had no effect on MBF in PT-Agtr1a-/-/PT-Nhe3-/- mice (n.s.). Taken together, these data support the hypothesis that intratubular Ang II, AT1a receptor, and its downstream target NHE3 may play an important role in the regulation of renal cortical and medullary blood flow under physiological conditions and during the development of Ang II-induced hypertension in mice. Funded by 2R01DK102429-03A1, 1R01DK123144-01, and 2R01DK067299-16A1 to Dr. Jia Zhuo). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.