Genetic Deletion of Angiotensinogen Selectively in the Proximal Tubule of the Kidneys Lowers Basal Blood Pressure but Does Not Attenuate Angiotensin II-Induced Hypertension in PT-Agt-/- Mice

Background: Angiotensinogen (AGT) is the sole substrate for the cascade of the renin-angiotensin-aldosterone system. Previous studies have shown that AGT is expressed only in the liver and AGT found in other tissues is reportedly derived only from the liver. However, whether AGT in the proximal tubules of the kidney plays a role in blood pressure regulation has not been studied. Methods: To determine whether AGT in the proximal tubules of the kidney plays any role in maintaining blood pressure homeostasis and the development of Ang II-induced hypertension, we generated a novel mouse model with proximal tubule-specific deletion of AGT in the kidney, PT-Agt-/-, using the iL-Sglt2-Cre and AGTflox/flox recombination approach. Results: Under physiological conditions, deletion of AGT selectively in the proximal tubules had no effects on body wt., kidney wt., and heart wt., as well as in hematocrit levels in PT-Agt-/- mice (n.s.). However, basal systolic and diastolic blood pressure were Δ13 ± 3 mmHg lower in adult male PT-Agt-/- mice than WT mice (P<0.01) without significantly altering heart rate (n.s.). To determine whether Ang II-induced hypertension is altered in PT-Agt-/- mice, we infused Ang II (~0.5 mg/kg/day, i.p., 2 weeks) to induce Ang II-induced hypertension. In response to Ang II infusion, systolic and diastolic blood pressure were markedly increased by Δ46 ± 3 mmHg in WT mice (P<0.01) and Δ38 ± 2 mmHg in PT-Agt-/- mice (P<0.01), respectively. No difference was found between WT and PT-Agt-/- mice. Interestingly, however, adenovirus-mediated, the Sglt2 promoter-driven overexpression of an intracellular Ang II fusion protein, Ad-Sglt2-ECFP/Ang II, selectively in the proximal tubules significantly restored blood pressure in PT-Agt-/- mice to the WT level (Δ117 ± 3 mmHg, P<0.01 vs. basal). Furthermore, ACE inhibition with captopril (25 mg/kg/day, p.o., 2 weeks) significantly decreased systolic and diastolic blood pressure by Δ34 ± 3 mmHg in PT-Agt-/- mice (P<0.01), and by Δ28 ± 3 mmHg in WT mice (P<0.01), respectively. Conclusion: In conclusion, our results suggest that AGT in the proximal tubules plays an important role in maintaining basal blood pressure homeostasis, but doesn't alter Ang II-induced hypertension or ACE inhibition. Funding: NIDDK Support