Angiopoietin-Like 4 Is a Potential Biomarker for Diabetic Kidney Disease Severity in Type 2 Diabetic Patients

Abstract

Background: Urinary angiopoietin-like protein 4 (ANGPTL4) levels were positively associated with the amount of albuminuria in streptozotocin (STZ)-injected rats and patients with type 2 diabetic mellitus (T2DM). We investigated the association of serum ANGPTL4 levels and the severity of diabetic kidney disease (DKD) in T2DM patients. Methods: Totalled 1207 T2DM patients were analysed in the cross-sectional study. DKD index included estimated glomerular filtration rate (eGFR), the stages of chronic kidney disease (CKD), and the grades of albuminuria. Normal-to-mild, moderate or severe albuminuria was defined by urinary albumin-to-creatinine ratio 300 mg/g, respectively. Serum levels of ANGPTL4 and other biomarkers were quantified by ELISA. Multivariable-adjusted linear and logistic analysis were performed to study the association of each biomarker with individual DKD index. ANGPTL4 expression was assessed in kidney sections and cultivated tubular cells by immunostaining and/or western blot. Findings: In 1207 T2DM patients (47·3% women, 57·7 ± 14·1 years), one-SD increased of the value of serum ANGPTL4 levels was associated with 6·62 ml/min/1·73m2 eGFR reduction (p<0·0001) and the odds ratios of having CKD vs. no CKD, normal-to-mild albuminuria vs. moderate, and moderate vs. severe albuminuria were 1·19 (p<0·0001), 1·05 (p=0·071) or 1·18 (p=0·0008), respectively. Compared with mice at 8 weeks old, db mice at 18 weeks old had increased ANGPTL4 expression in glomeruli and tubular cells. In vitro, glucose stimulated ANGPTL4 expression in tubular cells in a dose-dependent manner. Interpretation: ANGPTL4 was a potent marker to reflect DKD severity and a therapeutic target for further intervention. Funding Statement: This work was supported by National Science Funding in China (#81470566 and #81670765) for Ying-Mei Feng. Declaration of Interests: All authors declare no conflict of interest. Ethics Approval Statement: The study involved was approved by the Institutional Review Boards of the Beijing Luhe hospital and Capital Medical University. All the patients provided written informed consent.