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

Background Previous studies demonstrated that angiotensin (Ang) III , not Ang II , is the predominant endogenous agonist for Ang type-2 receptor ( AT ₂R)-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 AT ₁R 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 AT ₂Rs 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⁺ ATP ase ( NKA ) from basolateral membranes of renal proximal tubule cells. Consistent with NHE -3 and NKA retraction, Ang III increased pS er⁵⁵²- NHE -3 and decreased pS er²³- NKA . In contrast, in SHR , intrarenal Ang III failed to induce AT ₂R translocation, NHE -3 or NKA retraction, pS er⁵⁵²- NHE -3 phosphorylation, or pS er²³- NKA dephosphorylation. Conclusions These results indicate impaired Ang III / AT ₂R signaling as a possible primary defect in prehypertensive SHR .