Free NGAL and NGAL-MMP9 Complex As Potential Biomarkers of Partial Deficiencies of Enzyme 11β-Hydroxysteroid Dehydrogenase Type 2 (11βHSD2)

Presentation Number: SUN 538
Date of Presentation: April 2nd, 2017

Cristian A Carvajal*1, Alejandra Tapia-Castillo1, Jaime I Lizama1, David Ortiz2, Carolina P Valdivia1 and Carlos E Fardella1
1Pontificia Universidad Catolica de Chile, Santiago, Chile, 2Pontificia Universidad Católica de Chile. Santiago, Chile, Santiago, Chile

Abstract

At least one third of general population has arterial hypertension (AH). Mineralocorticoid arterial hypertension (MAH) has been highlighted as a prevalent secondary form of hypertension. In this way, severe and partial deficiency of enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) has been identified as pathogenic disorder leading to an impaired activation of mineralocorticoid receptor (MR) by cortisol (F). Activated MR lead to sodium reabsorption, vascular abnormalities and further changes in blood pressure (BP). Active seeking of biochemical and (epi)-genetic markers are devoted to find preclinical evidences of hypertensive disease. Free NGAL and its complex NGAL-MMP9 are thought to be potential biomarkers to mineralocorticoid AH.

Aim: To evaluate NGAL and NGAL-MMP9 as biomarker of subjects with partial deficiency of enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2).

Subjects and Methods: We design a cross-sectional study with 72 children (5-18 years) and 95 adult subjects (18-60 years). We measured clinical (BMI, BP) and biochemical variables as serum cortisol (F), cortisone (E) by LC-MS/MS, plasma aldosterone (PA), plasma renin activity (PRA), urinary sodium (Na) and potassium (K). We determined the normal values for all those variables, identifying p25, p50 and p75. We compared either pediatrics or adults subjects grouping by its upper quartile for F/E (>p75) and lower quartile for E (<p25) (subjects with suggested 11BHSD2 deficiency) vs. a control group (F/E(<p75), E(>p25)) matched by sex, age and BMI. In both groups measured and compared serum NGAL and NGAL/MMP-9 complex using an ELISA kit (R&D). Results are expressed as median [Q1-Q3], comparisons by Mann-Whitney test and associations by Spearman correlation (Rho). Odds ratio (OR) analyses were also performed with Prism 7.0.

Results: Children with both high-F/E & low-E (9/72; 12.5%) vs control showed high levels of free NGAL (128.7 [99.9-161.8] vs 80.8 [65.8-119.0] ng/ml; p<0.05) and NGAL/MMP-9 complex (45.4 [26.4-62.5] vs (19.5 [15.7-36.6] ng/mL; p <0.05). Adults with both high-F/E & low-E (17/95; 17.8%) vs control showed similar levels of free NGAL (122.8 [99.2-140.8] vs. 121.6 [89.4-138.3] ng/mL; p NS) and high NGAL/MMP-9 levels (60.7[32.7-81.3] vs 35.0[22.8-52.6] ng/ml; p<0.05). Taking together both children and adults, we observed F/E ratio positively associated to NGAL (Rho = 0.19; p 0.02) and NGAL/MMP-9 (Rho = 0.31; p 0.001). OR analyses of all subjects with high-F/E & low-E, and high NGAL is 2.7 (p 0.103) and with high NGAL/MMP9 complex is 2.71 [1.046-6.901](p 0.045).

Conclusion: Partial deficiencies in 11BHSD2 enzyme, evaluated by a biochemical screening based in high serum F/E with concomitant low E, is associated to high levels of NGAL and NGAL-MMP9, suggesting that both biomarkers can be useful to identify subjects with partial deficiencies in 11BHSD2.

 

Nothing to Disclose: CAC, AT, JIL, DO, CPV, CEF