AT₂R activation counteracts hypertension

Sustained activation of the renin–angiotensin system (RAS), which controls Na⁺ excretion and blood pressure (BP), by infusion of angiotensin II (ang II), leads to Na⁺ retention and hypertension in rats. New data from Robert Carey and colleagues show that C-21, a highly selective angiotensin AT₂ receptor (AT₂R) agonist, induces natriuresis and lowers blood pressure in rats with ang II-induced hypertension.

Credit: Lara Crow/NPG

The researchers previously reported that acute AT₂R activation with C-21 induced natriuresis in wild-type rats. “Because our previous work showed that AT₂R is active mainly when the RAS is activated, we hypothesized that activation of the AT₂R with C-21 in a model of ang II-dependent hypertension would reduce BP by increasing Na⁺ excretion,” explains Carey. Indeed, the researchers found that activation of AT₂R by systemic and renal C-21 administration prevents the initial renal Na⁺ retention seen with ang II infusion and lowers BP over the 7 days of ang II exposure. C-21 was equally effective in lowering BP whether administered before or 3 d after ang II exposure. “Importantly, we showed that ang II-induced hypertension cannot only be prevented but also treated after the hypertension is established,” says Carey.

ang II-induced hypertension can not only be prevented but also treated after the hypertension is established

To investigate the cellular mechanisms by which C-21 administration normalizes BP and natriuresis, Carey and colleagues monitored the cellular trafficking of AT₂R and two major renal proximal tubule sodium transporters, sodium–hydrogen exchanger 3 (NHE-3) and sodium–potassium-transporting ATPase (NKA). They found that C-21 increases Na⁺ excretion and lowers BP by internalizing and inactivating NHE-3 and NKA. “We also found that the effect of C-21 is likely to be reinforced by recruitment of AT₂R to the apical plasma membrane of renal proximal tubule cells, where binding to the agonist can occur,” adds Carey.

Natriuresis induced by C-21 was additive to the effects of diuretics that act in the distal tubule (chlorothiazide) or the cortical collecting duct (amiloride), suggesting that C-21 inhibits Na⁺ transport specifically in the renal proximal tubule. “AT₂R agonists might reinforce diuresis and natriuresis when combined with other existing diuretics,” says Carey.

The researchers now plan to investigate the effects of C-21 in rats exposed to desoxycorticosterone acetate and salt, a volume expansion model of hypertension, and in the transgenic m(Ren 2)27 rat, in which tissue-specific overexpression of components of the RAS causes hypertension.