Key result
Renal interstitial Ang III increased urine sodium excretion in 4-week-old Wistar Kyoto rats but failed to induce natriuresis in 4-week-old spontaneously hypertensive rats.
Why the study?
Hypertensive 12-week-old spontaneously hypertensive rats lack natriuretic responses to angiotensin III, but whether prehypertensive rats already exhibit defective natriuresis and the underlying mechanisms remained unknown.
Does renal interstitial Angiotensin III induce natriuresis and AT2R signaling in prehypertensive spontaneously hypertensive rats compared to Wistar Kyoto rats?
Does renal interstitial Angiotensin III induce natriuresis and AT2R signaling in prehypertensive spontaneously hypertensive rats compared to Wistar Kyoto rats?
Prehypertensive spontaneously hypertensive rats exhibit impaired Angiotensin III/AT2 receptor signaling, suggesting this defect may be a primary mechanism in the development of hypertension.
Defective Ang III-AT2R natriuresis in prehypertensive SHR is hypothesis-generating; human relevance and therapeutic implications remain open.
Background Previous studies demonstrated that angiotensin (Ang) III , not Ang II , is the predominant endogenous agonist for Ang type‐2 receptor ( AT 2 R)‐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 1 R 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 2 Rs 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 er 552 ‐ NHE ‐3 and decreased pS er 23 ‐ NKA . In contrast, in SHR , intrarenal Ang III failed to induce AT 2 R translocation, NHE ‐3 or NKA retraction, pS er 552 ‐ NHE ‐3 phosphorylation, or pS er 23 ‐ NKA dephosphorylation. Conclusions These results indicate impaired Ang III / AT 2 R signaling as a possible primary defect in prehypertensive SHR .
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Kemp et al. (2019) studied Prehypertension. Renal interstitial infusions of Ang III vs. Vehicle infusion was evaluated on Urine sodium (Na+) excretion. Renal interstitial Ang III increased urine sodium excretion in 4-week-old Wistar Kyoto rats but failed to induce natriuresis in 4-week-old spontaneously hypertensive rats.
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