Identification of Fatty Acid-Binding Protein 4 as a Potential Biomarker and Therapeutic Target for Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.

IF 3.2 4区 医学 Q1 UROLOGY & NEPHROLOGY
Kidney Diseases Pub Date : 2025-02-05 eCollection Date: 2025-01-01 DOI:10.1159/000543940
Lu Cheng, Qian Ren, Jing Liu, Mei-Lian Yu, Rong-Shuang Huang, Fan Guo, Liang Ma, Shen-Ju Gou, Ping Fu
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引用次数: 0

Abstract

Introduction: Fatty acid-binding protein 4 (FABP4) is a novel adipokine that is critically involved in many inflammatory and immune diseases. However, the role of FABP4 in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) remains unclear. The current study aimed to investigate the role of FABP4 in patients with ANCA-GN.

Methods: Plasma and urine samples from 37 patients with active ANCA-GN and kidney biopsy specimens from another group of 56 patients with ANCA-GN were collected. The plasma and urinary levels of FABP4 were measured by enzyme-linked immunosorbent assay and the kidney FABP4 expression was determined by immunohistochemistry and immunofluorescence staining. Associations between FABP4 levels with clinical and pathologic parameters were analyzed. To further elucidate the role of FABP4 in ANCA-GN, a novel FABP4 inhibitor, BMS309403, was employed 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), estimated glomerular filtration rate (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.

Conclusions: Urinary FABP4 levels might reflect the disease activity and renal involvement of ANCA-associated vasculitis, and FABP4 might act as a promising therapeutic target against ANCA-GN.

脂肪酸结合蛋白4作为抗中性粒细胞细胞质抗体相关肾小球肾炎的潜在生物标志物和治疗靶点的鉴定。
脂肪酸结合蛋白4 (Fatty acid binding protein 4, FABP4)是一种新型脂肪因子,在许多炎症和免疫疾病中起重要作用。然而,FABP4在抗中性粒细胞胞浆抗体(ANCA)相关性肾小球肾炎(ANCA- gn)中的作用尚不清楚。本研究旨在探讨FABP4在ANCA-GN患者中的作用。方法:收集37例活动性ANCA-GN患者的血浆和尿液标本,另一组56例ANCA-GN患者的肾脏活检标本。采用酶联免疫吸附法检测血浆和尿液中FABP4的水平,采用免疫组织化学和免疫荧光染色法检测肾脏中FABP4的表达。分析FABP4水平与临床和病理参数的关系。为了进一步阐明FABP4在ANCA-GN中的作用,我们将一种新的FABP4抑制剂BMS309403应用于公认的实验性自身免疫性血管炎(EAV)大鼠模型。结果:活动性ANCA-GN患者血浆和尿中FABP4水平显著高于正常对照组(52.8±23.6 ng/mL vs. 16.9±8.8 ng/mL, p < 0.01);中位数126.6(四分位数间距[IQR] 28.4-311.2) ng/g Cr vs中位数0.0 (IQR为0.0-0.0)ng/g Cr, p均< 0.01}。免疫组化分析显示,ANCA-GN患者肾小球和肾小管FABP4的表达高于正常对照组(0.015±0.012 vs. 0.004±0.003,p < 0.001;0.053±0.026 vs. 0.011±0.010,p < 0.001)。此外,对于ANCA- gn患者,活动性ANCA患者尿FABP4水平显著高于缓解性ANCA患者(184.3±187.0 ng/g Cr vs. 9.4±23.9 ng/g Cr, p < 0.01)。相关分析表明,尿与血清肌酐水平的FABP4相关(r = 0.596, p < 0.0001),尿白蛋白/ Cr (r = 0.523, p = 0.001),血中性粒细胞比值(r = 0.386, p = 0.018), PT (r = 0.583, p = 0.001), APTT (r = 0.364, p = 0.034),血红蛋白水平(r = -0.398, p = 0.015),肾小球滤过率(r = -0.680, p < 0.0001),新月比例(r = 0.661, p = 0.032),和全因死亡ANCA-GN患者(HR 2.93, 95% CI[1.05 - -8.19])。此外,BMS309403抑制FABP4可改善ANCA-GN大鼠的肾损伤。结论:尿液FABP4水平可能反映anca相关性血管炎的疾病活动性和肾脏受累情况,FABP4可能作为一种有希望的治疗ANCA-GN的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Kidney Diseases
Kidney Diseases UROLOGY & NEPHROLOGY-
CiteScore
6.00
自引率
2.70%
发文量
33
审稿时长
27 weeks
期刊介绍: ''Kidney Diseases'' aims to provide a platform for Asian and Western research to further and support communication and exchange of knowledge. Review articles cover the most recent clinical and basic science relevant to the entire field of nephrological disorders, including glomerular diseases, acute and chronic kidney injury, tubulo-interstitial disease, hypertension and metabolism-related disorders, end-stage renal disease, and genetic kidney disease. Special articles are prepared by two authors, one from East and one from West, which compare genetics, epidemiology, diagnosis methods, and treatment options of a disease.
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