Angiotensin subtype-2 receptors inhibit renin biosynthesis and angiotensin II formation

Renin is regulated by angiotensin subtype 1 (AT₁) receptor, but it is unknown whether angiotensin subtype 2 (AT₂) receptor contributes to this regulation. We hypothesized that AT₂ receptors inhibit angiotensin II (Ang II) through inhibition of renin biosynthesis. We monitored changes in renal Ang II, renin mRNA and protein expression, and plasma renin concentration (PRC) in response to renal cortical administration of the AT₁ receptor blocker valsartan or the AT₂ receptor blocker PD 123319 (PD) in conscious rats administered low sodium intake (LS). Renal interstitial Ang II increased by 47-fold in response to LS and increased further in response to valsartan or PD by 67-fold and 61-fold from normal sodium diet (NS) and by ≈41% and 29% from LS, respectively. Renin mRNA increased 63% during LS, and either valsartan or PD increased it further by 600% and 250% from NS and 538% and 187% from LS, respectively. Similarly, renal renin content and PRC increased in response to LS and increased further in response to combined LS and valsartan or PD administration. Immunostaining for renal renin protein demonstrated an increase in its expression in juxtaglomular and tubular cells during LS and increased further during AT₁ or AT₂ receptor blockade. These data demonstrate for the first time to our knowledge that AT₂ receptors regulate the renin-angiotensin system activity via inhibition of renin synthesis.