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

Abstract

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.

Fatty Acid-Binding Protein 4—An “Inauspicious” Adipokine—In Serum and Urine of Post-Partum Women with Excessive Gestational Weight Gain and Gestational Diabetes Mellitus

“…Our study is probably the first to report the urine FABP4 levels in the early puerperal mothers, yet we did not find any significant differences in this parameter between the healthy, EGWG, and GDM women. Urine, as a material for the assessment of FABP4 concentrations in the human studies, has been used in patients with glomerular injury, as well as with acute and chronic renal dysfunction [23,24,25]. Due to its small molecular size, this protein may escape the glomerular sieves and be excreted in the urine if not reabsorbed by the renal tubules.…”

“…However, the evaluation of FABP4 in the early post-partum period has not been performed so far. Furthermore, available studies on the urine FABP4 concentrations are limited to the patients with acute and chronic renal dysfunction [23,24,25]. As far as we know, the FABP4 levels in the urine of both GDM patients and EGWG women have not been investigated before.…”

Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria

“…Circulating FABP4 has been reported to be processed by the kidney and reabsorbed through megalin, an endocytic receptor expressed in proximal tubule epithelial cells [ 34 ]. It has also been shown that U-FABP4 is increased before an increase in serum creatinine, clusterin or cystatin C in a drug-induced glomerulonephritis model with N-phenylanthranilic acid and puromycin in in vivo and in vitro studies [ 35 ]. Newly expressed and secreted FABP4 in the glomerulus may pass through glomerular filtration barriers, and an excess of FABP4, which exceeds the permissible amount of reabsorption in proximal tubular cells, is excreted into urine, resulting in reflection of the extent of glomerular injury.…”

Phosphoprotein expression profiles in rat kidney injury: Source for potential mechanistic biomarkers

“…Here, we analysed three rat models of DIKI using phosphoprotein microarrays. Cisplatin, puromycin and NPAA were selected based on their ability to induce proximal tubule, glomerular and collecting duct injury respectively . This allowed us to identify phosphoprotein signatures associated with region‐specific kidney injury.…”

“…This might be a consequence of a recovery from injury after a single administration of cisplatin confirmed by the lack of histopathological lesions in proximal tubules on day 28. 5 Contrary to cisplatin, daily administration of puromycin resulted in the number of dysregulated phosphoproteins increasing over time.…”