Processing of Angiotensinogen to Angiotensin‐(1–12) by a Non‐ Renin Enzyme in the Salt‐Sensitive mRen2.Lewis Rat

Abstract

The mRen2.Lewis (mRen2) congenic rats exhibit a marked salt‐sensitive response in regards to blood pressure, oxidative stress, and proteinuria. The expression of renin within the kidney of the mRen2 is suppressed which likely reflects the intact response to the higher blood pressure; however, the urinary excretion of angiotensinogen (Aogen), Ang II and Ang‐(1–7) is significantly increased in high salt (HS) fed mRen2. The present study examined the renal response to a HS diet (4% Na) in female mRen2 regarding the urinary components of the renal RAS. In comparison to normal salt (0.5% Na), the HS diet markedly increased the urinary excretion of Aogen [1.8 ± 0.2 vs. 0.01 ± 0.001 μg/kg/day, p<0.01] and Ang‐(1–12) [4.6 ± 1.1 vs. 164 ± 21 pmol/kg/day; p<0.01]; however, Ang I excretion was not changed. Pooled and concentrated samples from the HS mRen2 were incubated with Aogen substrate (pH 7.0, 37ºC) and the generation of Ang‐(1–12) and Ang I determined by separate RIAs. Ang‐(1–12) was the predominant product from Aogen [1.2 pmols/min] as compared to Ang I [0.05 pmols/min]. HPLC analysis of the enzyme assay revealed a single immunoreactive peak for Ang‐(1–12). Although Ang I generation was abolished by the renin inhibitor aliskserin, the formation of Ang‐(1–12) was slightly enhanced. We conclude that the processing of Aogen to Ang‐(1–12) in the salt‐sensitive mRen2 likely reflects a renin‐independent pathway within the kidney.