Association Between the Natriuretic Action of Angiotensin-(1-7) and Selective Stimulation of Renal Prostaglandin I ₂ Release

Abstract

We previously reported that angiotensin-(1-7) [Ang-(1-7)], a heptapeptide derived from the metabolism of either Ang I or Ang II, was biologically active in the rat isolated kidney, producing a marked diuresis and natriuresis that could be dissociated from the modest increase in glomerular filtration rate. The natriuretic response was accompanied by an increase in sodium concentration and concomitant decrease in urinary potassium concentration. Ang-(1-7) has also been shown to stimulate arachidonic acid release from isolated proximal tubules and elicit prostaglandin release from a number of tissues. Therefore, in the present study we tested the hypothesis that prostaglandins participate in the renal actions of Ang-(1-7). Rat isolated kidneys were perfused at 37 degrees C with gassed (95% O2/5% CO2) Krebs-Henseleit buffer containing oncotic agents and amino acids for six 10-minute clearance periods at a constant pressure of 90 mm Hg. Ang-(1-7) was infused at a rate that achieved a final concentration of 3 pmol/mL in the presence and absence of 10 mumol/L indomethacin. Prostaglandin E2 (PGE2) and PGI2 released into ureteral and venous effluents were measured by enzyme-linked immunoassay. During Ang-(1-7) infusion there was a selective increase in 6-keto-PGF1 alpha, an index of PGI2, appearing in both urine and perfusate; PGE2 levels were unchanged. Inhibition of stimulated 6-keto-PGF1 alpha release with indomethacin halved the fourfold increase in urine flow and sevenfold increase in sodium excretion rate without altering the increase in urinary sodium concentration produced by Ang-(1-7).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal actions of angiotensin-(1-7)

“…22) administration of the selective Ang-(1-7) antagonist A-779 to conscious rats produced a significant increase in creatinine clearance. Conversely, small increases in GFR following Ang-(1-7) infusion were reported in isolated rat kidneys (16,48). The results obtained in our laboratory using anesthetized rats, and by others in isolated rat kidneys suggest that the glomerular actions of Ang-(1-7) are significantly blunted by kidney denervation and anesthesia.…”

“…In that study pretreatment with the cyclo-oxygenase inhibitor indomethacin potentiated the antidiuretic effect of Ang-(1-7) (22). In addition, in vitro studies also provided evidence for an interaction between Ang-(1-7) and prostaglandins at the renal tubular level (18,48). Using cultured renal epithelial cells, Andreatta-Van Leyen et al (18) observed that Ang-(1-7) significantly increased phospholipase A 2 activity and suggested that this heptapeptide may be involved in the regulation of electrolyte transport in proximal tubular epithelium by phospholipase A 2 activation.…”

“…Evidence for the participation of a signal transduction pathway for Ang-(1-7) mediated by phospholipase A 2 in the kidneys was provided by Andreatta-Van Leyen et al (18). Indirect evidence for such pathway was obtained by Hilchey et al (48) and Santos et al (22) (see above). The observation that the increase in water permeability induced by Ang-(1-7) in IMCD is blocked by the protein-kinase A inhibitor H8 (Magaldi AJ, personal communication) suggests that a signal transduction pathway mediated by adenylate cyclase also contributes to the effects of Ang-(1-7) in the kidney.…”

“…Using cultured renal epithelial cells, Andreatta-Van Leyen et al (18) observed that Ang-(1-7) significantly increased phospholipase A 2 activity and suggested that this heptapeptide may be involved in the regulation of electrolyte transport in proximal tubular epithelium by phospholipase A 2 activation. Hilchey et al (48), using isolated perfused kidney, reported that Ang-(1-7) selectively stimulated renal PGI 2 and suggested that this effect may be related to the natriuresis observed during Ang-(1-7) infusion.…”

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

“…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]. Taken together, these results suggest that in the proximal tubule, ANG-(1-7) affects natriuresis and diuresis by activating Mas receptors.…”