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.