Key Points
- To determine whether plasma angiotensinogen concentrations alter the metabolic clearance rate and circulatory half-life of renin.
- Infused human renin (30,000 pg), with or without the renin inhibitor remikiren, into transgenic rat strains expressing high (68±18 µg angiotensin I/mL) or low (10±4 µg angiotensin I/mL) human angiotensinogen and nontransgenic controls.
- Assessed renin clearance using direct radioimmunoassays, enzyme kinetic assays, and radiolabeled tracer distribution.
- Crossed homozygous human angiotensinogen transgenic rats with homozygous human renin transgenic rats to observe offspring plasma renin activity, renin concentrations, and blood pressure.
- Terminal half-life of human renin increased (130 vs 82 minutes) and metabolic clearance rate decreased (0.83±0.29 vs 2.2±0.66 µL·min⁻¹·g⁻¹) in the high-angiotensinogen strain compared to the low-angiotensinogen strain.
- Inhibition of renin with remikiren eliminated clearance rate and half-life differences between strains, rendering values similar to controls.
- Crossbred offspring with high angiotensinogen exhibited markedly elevated plasma renin activity, elevated renin concentration, and increased blood pressure despite feedback downregulation of renin genes.
Structured PICO
Does angiotensinogen concentration influence renin clearance in transgenic rats?
PPopulation2 transgenic rat (TGR) strains for human (h) AGT (one with high hAGT, one with low hAGT) and nontransgenic controls
IInterventionBolus infusion of human renin (hREN, 30,000 pg)
CComparatorLow hAGT strain and nontransgenic controls
OOutcomeTerminal half-life (T1/2beta) and metabolic clearance rate (MCR) of reninsurrogate
Increased angiotensinogen concentrations decrease renin metabolic clearance rate and increase its half-life, suggesting AGT is not merely a passive substrate but actively regulates renin kinetics and blood pressure.