Journal of the American Society of Hypertension
Research articleUrinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases
Introduction
The renin-angiotensin system (RAS) is well known to play an important role in blood pressure (BP) regulation and fluid and electrolyte homeostasis.1 In recent years, the focus of interest on the RAS has shifted to a main emphasis on the role of the local/tissue RAS in specific tissues.2 Emerging evidence has demonstrated the importance of the tissue RAS in the brain,3 heart,4 adrenal glands,5 vasculature,6, 7 as well as the kidneys.1 There is substantial evidence that the major fraction of angiotensin (Ang II) present in renal tissues is generated locally from angiotensinogen (AGT) delivered to the kidney as well as from AGT locally produced by proximal tubule cells.8 Renin secreted by the juxtaglomerular apparatus cells into the renal interstitium and vascular compartment also provides a pathway for the local generation of Ang I.9 Angiotensin-converting enzyme (ACE) is abundant in the kidney and is present in proximal tubules, distal tubules, and the collecting ducts.10 Ang I delivered to the kidney can also be converted to Ang II.11 Therefore, all of the components necessary to generate intrarenal Ang II are present along the nephron.1
Chronic kidney disease (CKD) is widely recognized as a major health problem all over the world. The renoprotective effects of ACE inhibitors and Ang II type 1 receptor blockers on CKD patients are established in diabetic nephropathy12, 13, 14, 15 as well as in nondiabetic nephropathy.16, 17 In order to account for these renoprotective effects, the activated intrarenal RAS was recently proposed to be involved in the progression of renal injury in CKD.18 The differential regulation of Ang II levels in plasma and kidney is now acknowledged.1, 18 Recently we reported that urinary excretion rates of AGT provide a specific index of intrarenal RAS status in Ang II-dependent hypertensive rats.19, 20, 21, 22, 23 We also recently reported that intrarenal AGT immunoreactivity is enhanced in IgA nephropathy patients.24 Moreover, intrarenal AGT immunoreactivity is significantly correlated positively with urinary occult blood, urinary protein-creatinine ratio (UPro/UCre), and serum creatinine, and correlated negatively with creatinine clearance.24 Recently, we provided evidence demonstrating that urinary AGT levels reflect intrarenal Ang II activity associated with increased risk for deterioration of renal function in CKD patients.25 However, in that study, AGT levels were measured by conversion assay.25 This conversion assay requires three steps. First, samples are incubated with and without exogenous renin. Then, Ang I concentrations in paired test tubes are measured by radioimmunoassay. Finally, converted Ang I is calculated as the difference between paired Ang I concentrations. Therefore, this conversion assay needs time-consuming procedures (∼2 days), indirect measurements, radioisotopes, and purified renin that is expensive and unobtainable. Meanwhile, we recently developed a direct quantitative method to measure plasma and urinary AGT using human AGT enzyme-linked immunosorbent assays (ELISAs).26 In contrast to the aforementioned conversion assay, the newly developed ELISA does not need time-consuming procedures (∼3 hours), indirect measurements, radioisotopes, or purified renin. These data prompted us to measure urinary AGT in CKD patients and investigate correlations with clinical parameters. Therefore, this study was performed to test a hypothesis that urinary AGT levels are enhanced in CKD patients and correlated with some clinical parameters.
Section snippets
Protocol
The experimental protocol of this study was approved by the Institutional Review Board of Hamamatsu University and Tulane University. Eighty patients with CKD and seven healthy volunteers were included in this study, and all samples were obtained with written informed consent. No subjects received ACE inhibitor or Ang II type 1 receptor blocker. The patients included 37 women and 43 men (from 18 to 94 years) and the volunteers included two women and five men (from 27 to 43 years). The
Distributions of Plasma and Urinary AGT Levels
Figure 1 illustrated distributions of plasma AGT levels (Figure 1A), urinary AGT-creatinine ratios (UAGT/UCre) (Figure 1B), and logarithmically transformed UAGT/UCre levels (Log[UAGT/UCre]) (Figure 1C), respectively. Plasma AGT levels showed a normal distribution (P = .4163); however, UAGT/UCre levels deviated from the normal distribution (P < .0001). When a logarithmic transformation was executed on UAGT/UCre levels, Log(UAGT/UCre) levels showed a normal distribution (P = .0540). Therefore,
Origin of Urinary AGT
Although most of the circulating AGT is produced and secreted by the liver, the kidneys also produce AGT.18 Intrarenal AGT mRNA and protein have been localized to proximal tubule cells indicating that the intratubular Ang II could be derived from locally formed and secreted AGT.29, 30 The AGT produced in proximal tubule cells appears to be secreted directly into the tubular lumen in addition to producing its metabolites intracellularly and secreting them into the tubular lumen.31 Proximal
Conclusions
Urinary AGT levels were investigated in CKD patients and control subjects. Urinary AGT levels were significantly correlated positively with UAlb/UCre, fractional excretion of sodium, UPro/UCre, and serum creatinine, and correlated negatively with eGFR. Urinary AGT levels were not correlated with age, gender, height, body weight, BMI, SBP, DBP, serum sodium levels, serum potassium levels, urinary sodium-creatinine ratios, plasma renin activity, or plasma AGT levels. Urinary AGT levels were
Acknowledgments
The authors acknowledge critical reviews and valuable comments of L. Gabriel Navar, PhD, Tulane University. The authors also acknowledge excellent technical assistance from My-Linh Rauv, Tulane University.
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This study was supported by Grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072408), the National Center for Research Resources (P20RR017659), and the National Heart, Lung, and Blood Institute (R01HL026371).
Conflict of interest: none.