Defective Renal Angiotensin III and AT2 Receptor Signaling in Prehypertensive Spontaneously Hypertensive Rats

Abstract

Background Previous studies demonstrated that angiotensin (Ang) III, not Ang II, is the predominant endogenous agonist for Ang type‐2 receptor (AT2R)‐induced natriuresis in normal rats, and that hypertensive 12‐week‐old spontaneously hypertensive rats (SHR) lack natriuretic responses to Ang III. This study tested whether prehypertensive SHR already have defective Ang III‐induced natriuresis and determined possible mechanisms. Methods and Results Female and male normotensive 4‐week‐old SHR and Wistar Kyoto rats were studied after 24‐hour systemic AT1R blockade. Left kidneys received 30 minute renal interstitial infusions of vehicle followed by Ang III (3.5, 7.0, 14, and 28 nmol/kg per min; each dose for 30 minutes). Right kidneys received vehicle infusions. In 4‐week‐old Wistar Kyoto rats, renal interstitial Ang III increased urine sodium (Na+) excretion but failed to induce natriuresis in 4‐week‐old SHR. Renal Ang III levels were similar between Wistar Kyoto rats and SHR, making increased Ang III degradation as a possible cause for defective natriuresis in SHR unlikely. In Wistar Kyoto rats, renal interstitial Ang III induced translocation of AT2Rs to apical plasma membranes of renal proximal tubule cells. Simultaneously, Ang III induced retraction of the major Na+ transporter Na+‐H+ exchanger‐3 (NHE‐3) from apical membranes and internalization of Na+/K+ATPase (NKA) from basolateral membranes of renal proximal tubule cells. Consistent with NHE‐3 and NKA retraction, Ang III increased pSer552‐NHE‐3 and decreased pSer23‐NKA. In contrast, in SHR, intrarenal Ang III failed to induce AT2R translocation, NHE‐3 or NKA retraction, pSer552‐NHE‐3 phosphorylation, or pSer23‐NKA dephosphorylation. Conclusions These results indicate impaired Ang III/AT2R signaling as a possible primary defect in prehypertensive SHR.

Keywords

• angiotensin
• angiotensin receptor
• hypertension
• natriuretic hormone
• renal physiology