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Hyperuricemia is an independent risk factor for chronic kidney disease (CKD). Excessive uric acid (UA) level in the blood leads to hyperuricemic nephropathy (HN), which is characterized by glomerular hypertension, arteriolosclerosis and tubulointerstitial fibrosis. Fatty acid binding protein 4 (FABP4) is a potential mediator of inflammatory responses which contributes to renal interstitial fibrosis. However, the roles of FABP4 in HN remains unknown. In the study, a mouse model of HN induced by feeding a mixture of adenine and potassium oxonate, severe kidney injury and interstitial fibrosis, as well as the increased kidney-expressed FABP4 protein level were evident, accompanied by the activation of inflammatory responses. Oral administration of BMS309403, a highly selective FABP4 inhibitor, improved renal dysfunction, inhibited the mRNA level of KIM-1 and NGAL, as well as reduced the expression of proinflammatory cytokines and fibrotic proteins in the injured kidneys. BMS309403 treatment also inhibited the FABP4 activity and further suppressed the activation of JAK2-STAT3 and NF-kB P65 signaling pathways in the hyperuricemia-injured kidneys and UA-stimulated human tubular epithelial (HK-2) cells, respectively. In summary, our study for the first time demonstrated that FABP4 played a crucial role in kidney inflammation and fibrosis via the regulation of JAK2-STAT3 and NF-kB P65 pathways in HN mice. The results suggested that FABP4 inhibition might be a promising therapeutic strategy for HN. Image 1 • Hyperuricemia is an independent risk factor for kidney inflammation and fibrosis. • FABP4 inhibition suppressed kidney inflammation and fibrosis in hyperuricemic mice. • FABP4 regulated JAK2-STAT3 and NF-κB signaling in kidneys of hyperuricemic mice. • FABP4 inhibition might be a therapeutic for hyperuricemic nephropathy. [ABSTRACT FROM AUTHOR]

Schematic diagram of Fabp4 in toxin induced nephropathy. Fabp4 regulated Pparγ and the phosphorylation of P65 and Stat3 to promote inflammation in toxin induced kidney injury and early fibrosis. [Display omitted] • Fabp4, highly expressed in kidney epithelia cells, is involved in toxins induced nephropathy; • Fabp4 inhibition reduced inflammation and early fibrosis in toxins induced kidney injury; • Fabp4 inhibition improved kidney injury via NF-κB and Stat3-mediated Pparγ activity; • Fabp4 might be a promising target for the treatment of toxins induced nephropathy; Considerable data have suggested that acute kidney injury (AKI) is often incompletely repaired and could lead to chronic kidney disease (CKD). As we known, toxin-induced nephropathy triggers the rapid production of proinflammatory mediators and the prolonged inflammation allows the injured kidneys to develop interstitial fibrosis. In our previous study, fatty acid-binding protein 4 (Fabp4) has been reported to be involved in the process of AKI. However, whether Fabp4 plays crucial roles in toxin-induced kidney injury remained unclear. To explore the effect and mechanism of Fabp4 on toxin induced kidney injury, folic acid (FA) and aristolochic acid (AA) animal models were used. Both FA and AA injected mice developed severe renal dysfunction and dramatically inflammatory response (IL-6, MCP1 and TNF-a), which further lead to early fibrosis confirmed by the accumulation of extracellular matrix proteins (α-Sma, Fn, Col1 and Col4). Importantly, we found that FA and AA induced-kidney injury triggered the high expression of Fabp4 mRNA/protein in tubular epithelial cells. Furthermore, pharmacological and genetic inhibition of Fabp4 significantly attenuated FA and AA induced renal dysfunction, pathological damage, and early fibrosis via the regulation of inflammation, which is mediated by suppressing p-p65/p-stat3 expression via enhancing Pparγ activity. In summary, Fabp4 in tubular epithelial cells exerted the deleterious effects during the recovery of FA and AA induced kidney injury and the inhibition of Fabp4 might be an effective therapeutic strategy against the progressive AKI. [ABSTRACT FROM AUTHOR]

Liriodendron chinense (Hemsl.) Sarg , known as the Chinese tulip tree, has a long history of cultivation and utilization in many Asia countries, especially in China to use in traditional Chinese medicine for expelling "wind and dampness", a term corresponding to rheumatic fever and rheumatoid arthritis. Interestingly, the barks of Liriodendron chinense (Hemsl.) Sarg was also found in folk to treat gout. However, further experimental studies remained to confirm its uric acid-lowering effects. The aim of the study was to evaluate the protective effect of ethanol extract of the barks of Liriodendron chinense (Hemsl.) Sarg (EELC) in a mouse model of hyperuricemic nephropathy (HN) and the involved mechanisms. EELC at a respective dose of 250 mg/kg/d or 500 mg/kg/d were orally administered to HN mice induced by a mixture of adenine (160 mg/kg/d)/potassium oxonate (2.4 g/kg/d) for 21 days. At the end of the treatment, serum uric acid, kidney functions (serum creatinine, blood urea nitrogen and urine microalbumin), 24-h urine uric acid excretion, as well as kidney pathological changes were investigated by biochemical assay, histopathological score, immunofluorescence and histochemistry, RT-qPCR, and western blotting analysis. Oral administration of EELC significantly lowered serum uric acid level at 500 mg/kg (185.75 ± 15.49 μmol/L of EELC vs. 238.28 ± 20.97 μmol/L of HN model, p < 0.01) in HN mice. EELC at 500 mg/kg also remarkably reduced the levels of serum creatinine (82.92 ± 7.86 μmol/L of EELC vs. 92.08 ± 6.13 μmol/L of HN model, p < 0.0001), blood urea nitrogen (21.50 ± 1.87 mmol/L of EELC vs. 29.40 ± 3.95 mmol/L of HN model, p < 0.001) and urine microalbumin (4.25 ± 0.40 mg/L of EELC vs. 5.95 ± 0.33 mg/L of HN model, p < 0.001) to improve renal function. It also attenuated renal fibrosis, especially the high-dose of EELC. Furthermore, EELC could inhibit the activation of NF-κB, ASK1/JNK/c-Jun, JAK2/STAT3 signaling pathways and reduce the release of pro-inflammatory cytokine TNF-α in the kidneys of HN mice. Additionally, EELC remarkably increased urine uric acid excretion of HN mice, which may be achieved by the upregulation of organic anion transporter 1 (OAT1), OAT3 and ATP-binding cassette subfamily G member 2 (ABCG2) proteins. EELC alleviated the progression of HN by suppressing the activation of NF-κB, ASK1/JNK/c-Jun and JAK2/STAT3 signaling pathway, reducing the infiltration of inflammatory factors and uric acid accumulation in the kidney. Image 1 [ABSTRACT FROM AUTHOR]