Urinary Angiotensinogen is Increased in Human Heart Failure

Abstract

Angiotensin II (AII) is an activator of the AT1 receptor and mediates deleterious actions in heart failure (HF) especially in the kidney. A major unmet need is a biomarker to assess intrarenal AII activity to optimize anti-AII therapies as well as serve as a possible biomarker for HF severity. Angiotensinogen (AGT) is the only known substrate of renin. Human AGT is converted to Angiotensin I by renin which is further converted by Angiotensin-converting enzyme to AII. Recent studies have established that AGT is present in proximal tubules and secreted into the tubular lumen and excreted in the urine. Increases in urinary AGT parallel increases in AII production in the kidney in renal disease and may be the key regulator of the renin angiotensin system (RAS) in the kidney. To date, urinary AGT in human HF is undefined. Urinary AGT is increased in patients with HF compared to normal human subjects. Our study recruited healthy subjects (Age 18-85) with no prescription medication use, and no history of HF or hypertension (n= 5) and hospitalized patients (Age 20 - 95) with acute decompensated HF (n= 5). Blood samples (EDTA) and 24 h urine samples were collected from normal and HF subjects. Twenty four hour urine samples were collected on ice and preserved with acetic acid. Blood was collected in EDTA vacutainers on ice. All aliquots were stored at -80°C until the time of assay. Angiotensinogen (AGT) was measured in EDTA-plasma and urine (24h) samples using the Human Total Angiotensinogen Assay Kit (IBL, Japan). Plasma AGT was expressed as mg/mL. Urinary AGT was normalized to respective urinary creatinine levels of each subject and expressed as AGT (ng/mg Ucre). Comparisons between two groups were performed using Student t-test. All values are expressed as Mean ±SD. P<0.05 was considered significant. Plasma AGT was not different between HF and normal subjects (56.0 ± 11.9 mg/mL vs 49.8 ±10.6 mg/mL). Importantly, urinary angiotensinogen in HF patients was increased compared to normal subjects (9.5 ±6.2 ng/mg Ucre vs 0.7 ± 0.3 ng/mg Ucre, P<0.05) and approximately 10 fold greater in HF than in normals. Urinary angiotensinogen is increased in HF patients in this proof of concept study when compared to normal subjects which may indicate increased intrarenal RAS activity. Further studies are needed to validate our findings and determine if use of urinary AGT may facilitate optimization of anti-AII therapies as well as serve as a renal biomarker for adverse outcomes in human HF.