Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis

Wang, Bo; Xu, Jun; Ren, Qian; Cheng, Lu; Guo, Fan; Liang, Yan; Yang, Luxi; Tan, Zhouke; Fu, Ping; Ma, Liang

doi:10.1038/s41419-022-04794-w

Cited by 33 publications

(22 citation statements)

References 45 publications

(71 reference statements)

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“…The regulation of inflammation and apoptosis seems to be strongly related since FABP4 silencing protects from cardiomyocyte or chondrocyte apoptosis via the master regulator of the inflammation nuclear factor-κB (NF-κB) pathway [ 15 , 27 ]. Conversely, the downregulation of FABP4 using its specific inhibitor BMS309403 can suppress inflammation and/or apoptosis in pathological settings including acute lung injury, acute kidney injury, or diabetic nephropathy [ 27 , 28 , 29 ]. Of interest, treatment with BMS309403 improves insulin resistance, diabetes mellitus, fatty liver disease, and atherosclerosis [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Garaikoetxea

Martín‐Núñez

Navarro

et al. 2022

IJMS

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Aortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS.

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Section: Discussionmentioning

confidence: 99%

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Garaikoetxea

Martín‐Núñez

Navarro

et al. 2022

IJMS

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“…27 Fatty acid-binding protein 4 mediates inflammatory response and cell apoptosis in sepsis-induced AKI, and might act as a novel therapeutic target for sepsisinduced AKI. 28 PHLDA1 is reported to be involved in OGD/ R-mediated neurons, 14 ulcerative colitis and dysplasia, 15 ovarian cancer, 16 and hepatic ischemia/reperfusion injury. 17 However, participation of PHLDA1 in sepsis-induced AKI remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

PHLDA1 knockdown inhibits inflammation and oxidative stress by regulating JNK/ERK pathway, and plays a protective role in sepsis-induced acute kidney injury

Gong

Wenmei

et al. 2022

Allergol Immunopathol

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Background: Acute kidney injury (AKI), a prevalent complication of sepsis, causes substantial burden on patients’ families as well as the society. More reliable markers are urgently required for the prevention and treatment of AKI. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) was implicated in various diseases, but its involvement in sepsis-induced AKI remains to be explored. The JNK/ERK pathway has been revealed as being involved in progression of sepsis. One previous study demonstrated that PHLDA1 could activate the JNK/ERK pathway in hepatic ischemia/reperfusion injury. Nevertheless, involvement of PHLDA1 in sepsis-triggered AKI through the JNK/ERK pathway has not been probed. Methods: A cecal ligation and punctured (CLP) mice model of sepsis-induced AKI was estab-lished. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence staining were applied to evaluate the expression of PHLDA1. Concentration of blood urea nitrogen (BUN) and serum creatinine (Scr), inflammation markers, including interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α, as well as oxidative stress-associated proteins (catalase, malondialdehyde, superoxide dismutase, and glutathione), in the kidney tissues of mice were evaluated by enzyme-linked-immunosorbent serologic assay. Western blot analysis was applied for measuring protein expression levels. Results: The BUN and SCr levels in mice were obviously elevated in the CLP group compared to the sham group. Moreover, the expression of PHLDA1 was also elevated in the CLP group in comparison to the sham group. Down-regulation of PHLDA1 alleviated renal injury, inflam-mation, and oxidative stress in AKI model. Mechanistic study showed that PHLDA1 knockdown suppressed the activation of c-JUN N-terminal kinase/p38 and extracellular signal-regulated kinase (JNK/ERK) pathway. Conclusion: Down-regulation of PHLDA1 suppressed inflammation and oxidative stress through the modulation of JNK/ERK pathway in sepsis-induced AKI. The results could offer a novel insight into the treatment of patients with sepsis-induced AKI.

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“…IRI model and CLP model were established as previously described. 54 , 55 The animal researches together with the details of the TEC-specific FFAR4 KO mice and FFAR4-KO mice production are concluded in the Supplementary Methods.…”

Section: Methodsmentioning

confidence: 99%

FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

Yang

Wang

Guo

et al. 2022

Sig Transduct Target Ther

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Acute kidney injury (AKI) is a serious clinical complication with high morbidity and mortality rates. Despite substantial progress in understanding the mechanism of AKI, no effective therapy is available for treatment or prevention. We previously found that G protein-coupled receptor (GPCR) family member free fatty acid receptor 4 (FFAR4) agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice. However, the versatile role of FFAR4 in kidney has not been well characterized. In the study, the expression of FFAR4 was abnormally decreased in tubular epithelial cells (TECs) of cisplatin, cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice. Notably, FFAR4, as a key determinant, was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, marker protein p53, p21, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs. These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

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Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis

Cited by 33 publications

References 45 publications

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis

PHLDA1 knockdown inhibits inflammation and oxidative stress by regulating JNK/ERK pathway, and plays a protective role in sepsis-induced acute kidney injury

FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

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