Overexpression of Renin in the Collecting Duct Causes Elevated Blood Pressure

Abstract

Renin is synthesized in the collecting duct and is regulated differently than renin in the juxtaglomerular apparatus. However, the physiological relevance of collecting duct renin remains unknown, particularly with regard to its ability to regulate blood pressure. We used gene targeting to generate mice with overexpression of renin in the collecting duct. A conditional mutant mouse line was created with the mouse renin transcript distal to a "transcriptional stop sequence" such that gene expression only occurred when the stop sequence was excised. These mice were bred with mice transgenic for the aquaporin-2 promoter driving Cre recombinase in order to achieve collecting duct-specific overexpression of renin. RNA analysis confirmed kidney-specific recombination, and medullary renin mRNA levels were increased 5-fold in collecting duct renin mice. Blood pressure was recorded by telemetry and plasma and urine was collected in 24-hour metabolic cages on normal, high-, and low-Na+ diets. Although no significant differences in 24-hour urinary Na+ excretion between targeted and control mice were detected, renin overexpresser mice had elevated blood pressure compared with controls on a high-Na+ diet. Urinary renin excretion was 2-fold higher in targeted mice as compared with controls on normal and low-Na+ diets. Plasma renin concentration was significantly suppressed in targeted mice as compared with controls on normal and high-Na+ diets. Taken together, these results suggest that collecting duct-derived renin has the potential to modulate blood pressure independent of the systemic renin-angiotensin system.