Abstract
Acute kidney injury (AKI) is a common and potentially life-threatening complication. Studies confirmed that circulating FABP4 depended on renal function of AKI patients. In our previous study, FABP4 was involved in the pathogenesis of I/R-induced AKI. However, the function of FABP4 in rhabdomyolysis-induced AKI remained poorly understood. In the study, we further investigated the effect of FABP4 in a murine model of glycerol injection-induced rhabdomyolysis. Following glycerol injection, the mice developed severe AKI as indicated by acute renal dysfunction and histologic changes, companied by the increased FABP4 expression in the cytoplasm of tubular epithelial cells. Pharmacological inhibition of FABP4 by a highly selective inhibitor BMS309403 significantly reduced serum creatinine level, proinflammatory cytokine mRNA expression of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein 1 as well as attenuated renal tubular damage in glycerol-injured kidneys. Oral administration of FABP4 inhibitor also resulted in a significant attenuation of ER stress indicated by transmission electron microscope analysis and its maker proteins expression of GRP78, CHOP, p-perk, and ATF4 in kidneys of AKI. Furthermore, BMS309403 could attenuate myoglobin-induced ER stress and inflammation in renal proximal tubular epithelial cell line (HK-2). Overall, these data highlighted that renal protection of selective FABP4 inhibitor was substantiated by the reduction of ER stress and inflammation in tubular epithelial cells of rhabdomyolysis-induced injured kidneys and suggested that the inhibition of FABP4 might be a promising therapeutic strategy for AKI treatment.
Highlights
Rhabdomyolysis is a syndrome characterized by the breakdown of skeletal muscle and leakage of the muscle cell contents such as myoglobin into the bloodstream (Bosch et al, 2009) and acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis (Raymond et al, 2000)
To determine whether the inhibition of Fatty acid-binding protein 4 (FABP4) exhibited a renal protective effect, we examined the function of BMS309403, FIGURE 2 | Glycerol-induced the upregulation of FABP4 expression in kidney. (A) Hotmap of differentially expressed genes between control and glycerol group. (B) The kidney tissue lysates were subjected to Western blotting analysis with indicated antibodies against FABP4 and the expressions of FABP4 was quantified by densitometry and normalized with GAPDH. (C) FABP4 mRNA expression in renal tissue was measured by real-time PCR. (D) Immunofluorescence staining of FABP4 and E-cadherin in the kidney tissue
FABP4 possessed a well-established role in the pathogenesis of diabetes and atherosclerosis (Furuhashi et al, 2007; Erbay et al, 2009), the effect of FABP4 in rhabdomyolysis-induced AKI has not been determined
Summary
Rhabdomyolysis is a syndrome characterized by the breakdown of skeletal muscle and leakage of the muscle cell contents such as myoglobin into the bloodstream (Bosch et al, 2009) and acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis (Raymond et al, 2000). The detailed mechanisms have not been fully comprehended, the endoplasmic reticulum (ER) stress and inflammation played crucial roles in rhabdomyolysis-induced AKI (Panizo et al, 2015; Feng et al, 2016). Initiation of canonical UPR engaged three distinct signaling pathways, which were regulated by pancreatic ER kinase (PERK), activating transcription factor-6 (ATF6), and inositolrequiring transmembrane kinase/endonuclease-1 (IRE-1) (Ron and Walter, 2007; Hotamisligil and Erbay, 2008). The elicitation of UPR in turn activated c-Jun N-terminal kinases (JNK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pro-inflammatory signaling pathways (Tam et al, 2012). The combined action of the three pathways contributed to the inhibition of protein translation, stimulation of protein degradation and production of chaperone proteins, triggering either recovery of ER function, inflammation or cell death (Zhang et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
