Issue 27, 2018, Issue in Progress

Pharmacological inhibition of fatty acid-binding protein 4 (FABP4) protects against renal ischemia-reperfusion injury

Abstract

Fatty acid-binding protein 4 (FABP4) is a key mediator of endoplasmic reticulum (ER) stress and apoptosis in diabetes and atherosclerosis. Studies also confirmed that circulating FABP4 depended on renal function in chronic kidney disease (CKD) and acute kidney injury (AKI) patients. However, the function of FABP4 in AKI remains poorly understood and the aim of this study was to investigate the role of FABP4 in ischemia-reperfusion (I/R)-induced AKI. In the present study, renal I/R injury triggered the high expression of the FABP4 gene and protein in the nucleus and cytoplasm of tubular cells of mouse kidney tissue compared to that of Sham. Pretreatment with BMS309403, a highly selective inhibitor of FABP4 at a dose of 20 mg kgāˆ’1 dāˆ’1 for 4 d, significantly reduced serum creatinine levels to improve acute renal dysfunction and attenuated renal tubular damage in injured kidneys. Pharmacological inhibition of FABP4 also decreased the number of TdT-mediated dUTP nick-end labeling (TUNEL) positive apoptotic tubular cells, accompanied by the down-regulation of cleaved-caspase-3 expression. Furthermore, oral administration of FABP4 inhibitor resulted in a significant attenuation of ER stress indicated by its maker proteins expression of glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and caspase-12 in I/R injured kidneys. In vitro, the increased expression of FABP4 in the human renal proximal tubule cell line (HK-2 cell) was induced by hypoxia followed by reoxygenation (HR) and the FABP4 inhibitor resulted in a significant attenuation of cell apoptosis and ER stress in HR-induced HK-2 cells. In summary, these findings indicated that FABP4 contributed to the pathogenesis of I/R-induced AKI and suggested that the inhibition of FABP4 might be a promising therapeutic strategy for AKI treatment.

Graphical abstract: Pharmacological inhibition of fatty acid-binding protein 4 (FABP4) protects against renal ischemia-reperfusion injury

Article information

Article type
Paper
Submitted
05 Jan 2018
Accepted
18 Apr 2018
First published
23 Apr 2018
This article is Open Access
Creative Commons BY license

RSC Adv., 2018,8, 15207-15214

Pharmacological inhibition of fatty acid-binding protein 4 (FABP4) protects against renal ischemia-reperfusion injury

M. Shi, R. Huang, F. Guo, L. Li, Y. Feng, Z. Wei, L. Zhou, L. Ma and P. Fu, RSC Adv., 2018, 8, 15207 DOI: 10.1039/C8RA00122G

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