Differential Regulation of Circulating and Urinary Renin-Angiotensin System in Acute Decompensated Heart Failure

Abstract

Introduction: An essential link between the kidney and heart in heart failure (HF) has long been known as has the importance of the renin-angiotensin system (RAS). Recent studies in renal disease and in experimental animal models points to existence of renal-specific RAS that may be independent of the circulating RAS and which may be a primary mechanism for renal dysfunction in cardiorenal disease states. Angiotensinogen (AGT) is the precursor peptide which is released by the liver but recent studies have reported its renal production. Due to its large size (453 amino acids) circulating AGT cannot be filtered by the glomerulus and thus urinary AGT (uAGT) is thought to be of renal origin. Angiotensin II (ANGII) (8 amino acids), is the effector peptide and exerts most of its pathological effects through the AT1receptor. The current study was focused on patients hospitalized for acute decompensated HF (ADHF). Hypothesis: The renal RAS and not the circulating RAS is activated based upon the measurement of plasma and urinary AGT and ANGII. Methods: Normal subjects (n = 45) with no history of heart disease, kidney disease or hypertension were recruited from the Mayo Clinic Biobank. ADHF subjects (n = 58) were recruited within 1–2 days of their admission. NTproBNP and urinary creatinine were measured using standard assays. Plasma and urinary AGT were measured using Elisa (IBL, Japan). Plasma and urinary ANGII were measured using RIA (Phoenix Pharmaceuticals, USA). Urinary values were indexed to urinary creatinine values. P < .05 was considered significant Results: Urinary AGT (uAGT) and Ang II (uANGII) were significantly elevated (P < .03) in HF subjects compared to normals after adjusting for age and gender. In contrast, plasma ANGII was not increased in ADHF and plasma AGT decreased. There was little to no correlation between uAGT or uANGII with urine volume(r = 0.11 and 0.06) and GFR (r=-0.19 and -0.23) in ADHF patients. Conclusions: In the setting of ADHF, urinary AGT and ANGII are elevated compared to normal subjects. The levels of uAGT and uANGII in ADHF subjects did not correlate with urinary creatinine, GFR, urine volume, suggesting that this increase is independent of kidney function and effect of diuresis in ADHF subjects. These findings collectively point to an activated intrarenal RAS, which may have a pathophysiological role in progression of ADHF and provides a potential renal therapeutic target for the treatment of ADHF.