Novel Aspects of Fatty Acid-Binding Protein 4 in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis

Background: Fatty acid-binding protein 4 (FABP4) has been extensively studied as an adipokine that regulates inflammation and immunometabolic diseases. The current study aimed to investigate the role of FABP4 in patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). Methods: Plasma and urine samples of 37 patients with active ANCA-GN and several sequential samples in remission stage of these patients were collected. Kidney biopsy specimens from 56 patients with active ANCA-GN were collected. The levels of FABP4 in plasma, urine and kidney biopsy specimen were detected and analyzed. The role of FABP4 by a highly selective inhibitor BMS309403 in ANCA-GN was primarily investigated in a recognized rat model of experimental autoimmune vasculitis (EAV). Results: Plasma and urinary levels of FABP4 in active ANCA-GN patients were significantly higher than those in normal controls (52.8 ± 23.6 ng/ml vs. 16.9 ± 8.8 ng/ml, P<0.01; median 126.6 [interquartile range (IQR) 28.4-311.2] ng/g Cr vs. median 0.0 [IQR 0.0-0.0] ng/g Cr, P<0.01, respectively). Immunohistochemical analysis revealed higher glomerular and tubular expression of FABP4 in the kidneys of ANCA-GN patients than those in normal controls (0.015 ± 0.012 vs. 0.004 ± 0.003, P<0.001; 0.053 ± 0.026 vs. 0.011 ± 0.010, P<0.001, respectively). Moreover, for ANCA-GN patients, urinary FABP4 levels were significantly higher in active ANCA than those in remission (184.3 ± 187.0 ng/g Cr vs. 9.4 ± 23.9 ng/g Cr, P<0.01). Correlation analysis showed that urinary levels of FABP4 correlated with serum creatinine (r=0.596, P<0.0001), urinary albumin/Cr (r=0.523, P=0.001), blood neutrophil ratio (r=0.386, P=0.018), PT (r=0.583, P=0.001), APTT (r=0.364, P=0.034), hemoglobin level (r=-0.398, P=0.015), eGFR (r=-0.680, P<0.0001), crescent proportion (r=0.661, P=0.032) and all-cause death of ANCA-GN patients (HR 2.93, 95%CI (1.05-8.19)). Furthermore, FABP4 inhibition by BMS309403 ameliorated renal injury in a rat mole of ANCA-GN. Conclusion: Urinary FABP4 was a potential noninvasive biomarker of disease activity and severity in ANCA-GN, and FABP4 might act as a promising therapeutic target against ANCA-GN. Funding: Government Support – Non-U.S.