Renal actions of angiotensin-(1-7): in vivo and in vitro studies

Abstract

In vivo studies were conducted in Na-replete anesthetized male Wistar rats with denervated kidneys. Intrarenal injections of angiotensin-(1-7) [ANG-(1-7) at > 1 nmol/kg produced a shallow dose-dependent decrease in renal blood flow that was mediated by the AT1-type ANG II receptor. A constant intrarenal infusion of ANG-(1-7) at 0.1 and 1 nmol.min-1.kg-1 had minimal effects on renal blood flow and blood pressure and resulted in an elevated urinary excretion of Na and water compared with the time-control saline-infused group. To determine whether ANG-(1-7) may have a direct action on tubular epithelium to inhibit Na reabsorption, we examined the effect of ANG-(1-7) on transport-dependent O2 consumption (Qo2) in fresh suspensions of rat proximal tubules in vitro. ANG-(1-7) inhibited Qo2 in a concentration-dependent fashion with a threshold concentration of approximately 100 pM. Stimulating Na-K-adenosinetriphosphatase (Na-K-ATPase) activity with nystatin caused a leftward shift of the inhibitory concentration-response curve to ANG-(1-7). The 22% inhibition of Qo2 by 1 pM ANG-(1-7) was abolished by pretreatment with 5 mM ouabain (Na-K-ATPase inhibitor), unaltered by pretreatment with 1 microM PD-123319 (AT2 receptor antagonist), partially attenuated by 1 microM losartan (AT1 receptor antagonist), and abolished by 1 microM [Sar1, Thr8]ANG II (nonselective ANG receptor antagonist). Together these findings indicate that ANG-(1-7) has biological activity in the kidney and, at nonvasoconstrictor doses, results in increased Na and water excretion in vivo. One site of action is the proximal tubule, where ANG-(1-7) can inhibit an ouabain-sensitive Na-K-ATPase exit step in cellular Na transport. This novel inhibitory action of ANG-(1-7) appears to be mediated by an AT1 receptor (minor component) and a non-AT1, non-AT2 ANG receptor (major component).

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…In anesthetized rats, administration of Ang-(1-7) increased urinary flow rate and sodium excretion, an effect abolished by the Ang-(1-7) receptor antagonist A-779 (ref. 146). However, the increase in urinary sodium and water excretion after intrarenal infusion of Ang-(1-7) in dogs was reduced by AT 1 , but not AT 2 receptor blockade, suggesting a role for Ang-(1-7)-mediated signaling via the AT 1 receptor.…”

“…139,144 Hypertensive animals treated with ACE inhibitors had a 25-to 50-fold increase of circulating levels of Ang-(1-7), suggesting that Ang-(1-7) might contribute to the antihypertensive effects produced by ACE inhibitors. [145][146][147] The role of Ang-(1-7) in the regulation of kidney function is not well understood and conflicting data were reported. Some groups failed to detect effects of Ang-(1-7) on RBF in rats, 145,148 but others observed a renal vasodilator response, and reported afferent arteriolar dilatation mediated by NO.…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…In isolated, perfused rat kidneys and anesthetized animals [172,173], ANG-(1-7) has been shown to increase sodium and water excretion and the glomerular filtration rate (GFR) without affecting renovascular resistance. Hence, it is also possible that ANG-(1-7) induces diuresis and natriuresis by inhibiting renal tubular Na+/K+-ATPase [174,175]. However, ANG-(1-7) also induced antidiuresis in water-loaded rodents (258) and increased renal tubular sodium reabsorption in rats [176].…”

“…In the proximal tubule of anesthetized animals, ANG-(1-7) increases urinary flow rates and sodium excretion. This effect was abolished by the Mas receptor antagonist A779 in rats [175], but in dogs, this hormonal effect was partially blocked by the AT1 receptor antagonist EXP 3174 but not by the AT2 receptor antagonist PD123319 [182]. In isolated rat proximal straight tubules, similar to ANG II, ANG-(1-7) exerts a biphasic effect through AT1 receptors.…”

“…In rabbit proximal tubular cells, ANG-(1-7) inhibits sodium reabsorption by activating phospholipase A2 [184]. In addition, in isolated basolateral membranes of kidney proximal tubules [175,185], ANG-(1-7) modulated the activity of Na + /K + -ATPase, and in isolated pig kidney inner cortical membranes [186], it inhibited Na + -ATPase activity via an effect that was reversed by an AT2 receptor antagonist. Furthermore, in isolated proximal tubules, i) ANG-(1-7) stimulated the release of arachidonic acid [184], and ii) the inhibition of prostaglandin release that resulted from COX inhibition attenuated the ANG-(1-7)-induced increase in urine flow and sodium excretion [187].…”