Abstract P433: Evidence For An Important Role Of AT1a Receptors In The Renomedullary Interstitial Cells In Basal Blood Pressure Homeostasis And The Development Of Angiotensin Ii-induced Hypertension

Abstract

The renomedullary interstitial cells (RMICs) are highly specialized lipid-laden interstitial fibroblasts, which form characteristic "ladder-like" structural associations with adjacent microvessels and renal tubules in the kidney medulla. We have previously reported that RMICs express abundant AT 1 (AT 1a ) receptors in vitro and in vivo , but the physiological role of AT 1 (AT 1a ) receptors in RMICs has not been determined. In the present study, we generated and phenotyped for the 1 st time a new mutant mouse model with RMIC-selective deletion of AT 1a receptors in the kidney medulla, RMIC- Agtr1a -/- , using an innovative inducible Tenascin-C-CreER2/Agtr1a f/f approach. Deletion of AT 1a receptors selectively in RMICs did not alter the development and cellular structures in the kidney medulla of RMIC- Agtr1a -/- mice. The heart wt. to body wt. ratio was lower ( P <0.01), whereas the kidney wt. to body wt. ratio was significantly higher ( P <0.01) in RMIC- Agtr1a -/- than wild-type (WT) mice without altering heart rate. Compared with WT mice, basal systolic, diastolic, and mean arterial blood pressure, as measured by the telemetry technique, were significantly lower in adult male RMIC- Agtr1a -/- mice (WT: 122 ± 3 mmHg vs. RMIC- Agtr1a -/- : 103 ± 4 mmHg, P <0.01). The decreases in basal blood pressure in RMIC- Agtr1a -/- mice was associated with significantly lower urine excretion (WT: 1.56 ± 0.15 mL/24 h vs. RMIC- Agtr1a -/- : 0.98 ± 0.13 mL/24 h, P <0.01), urinary sodium (WT: 207.9 ± 7.3 μmol/24 h vs. RMIC- Agtr1a -/- : 145.2 ± 5.4 μmol/24 h, P <0.01), potassium excretion (WT: 221.0 ± 6.7 μmol/24 h vs. RMIC- Agtr1a -/- : 160.8 ± 10.6 μmol/24 h, P <0.01), and markedly decreased urine osmolality in RMIC- Agtr1a -/- mice (WT: 1724 ± 335 mOsm/Kg H 2 O vs. RMIC- Agtr1a -/- : 1128 ± 102 mOsm/Kg H 2 O, P <0.01). Ang II infusion (0.5 mg/kg/day, i.p., 2 weeks) increased blood pressure to 148 ± 5 mmHg in WT mice, as expected, but it increased only to 129 ± 8 mmHg without further altering urine osmolality from controls in RMIC- Agtr1a -/- mice ( P <0.01). In conclusion, the present study provides new evidence for the 1st time for an important role of AT 1a receptors in RMICs in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.