Fatty-Acid Binding Protein 4 (FABP4) as a Potential Preclinical Biomarker of Drug-Induced Kidney Injury

摘要

Identification of improved translatable biomarkers of nephrotoxicity is an unmet safety biomarker need. Fatty-acid-binding protein 4 (FABP4) was previously found to be associated with clinical renal dysfunction and was proposed as a biomarker of glomerular damage. The aim of this study was to evaluate FABP4 as a potential preclinical biomarker of drug-induced kidney injury (DIKI). Han-Wistar rats were dosed with cisplatin [2.5 mg/kg, single, intraperitoneally (i.p.)], puromycin (10 mg/kg, daily, i.p.) or N-phenylanthranylic acid [NPAA, 500 mg/kg, daily, per os (p.o.)] over a 28-day period to induce proximal tubule, glomerular or collecting duct injury, respectively. An increase in urinary FABP4 levels was observed on days 1 and 3 after NPAA treatment and on days 14, 21, and 28 after puromycin treatment, whereas cisplatin treatment had no effect. No significant changes were reported for plasma levels of FABP4 after any treatment. Interestingly, immunohistochemical analysis showed a marked decrease in FABP4 expression in the loop of Henle on day 7 after NPAA treatment and a complete loss of FABP4 expression on day 14 after puromycin treatment. The magnitude of increase in FABP4 urinary levels in response to NPAA and puromycin was higher than for established preclinical biomarkers serum creatinine, clusterin, or cystatin C. Our results suggest that FABP4 has the potential for preclinical application as a biomarker of DIKI.