RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

Abstract

Fatty acid binding protein 4 (FABP4), a subtype of fatty acid-binding protein family, shows critical roles in metabolism and inflammation. However, its roles on regulating renal interstitial fibrosis (RIF) remain unclear. In this work, LPS-stimulated in vitro models on NRK-52E and NRK-49F cells, and in vivo UUO models in rats and mice were established. The results showed that comparing with control groups or sham groups, the expression levels of α-SMA, COL1A, COL3A, IL-1β, IL-6, and TNF-α in LPS-stimulated cells or UUO animals were significantly increased. Meanwhile, the levels of TC, TG, and free fatty acid were also significantly increased as well as the obvious lipid droplets, and the serum levels of BUN, Cr were significantly increased with large amounts of collagen deposition in renal tissues. Further investigation showed that compared with control groups or sham groups, the expression levels of FABP4 in LPS-stimulated cells and UUO animals were significantly increased, resulting in down- regulating the expression levels of PPARγ, upregulating the levels of p65 and ICAM-1, and decreasing the expression levels of ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1. To deeply explore the mechanism of FABP4 in RIF, FABP4 siRNA and inhibitor interfered cell models, and UUO model on FABP4 knockout (KO) mice were used. The results showed that the expression levels of α-SMA, COL1A, and COL3A were significantly decreased, the deposition of lipid droplets decreased, and the contents of TC, TG, and free fatty acids were significantly decreased after gene silencing. Meanwhile, the expression levels of PPAR-γ, ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1 were upregulated, the levels of p65 and ICAM-1 were downregulated, and the mRNA levels of IL-1β, IL-6, and TNF-α were decreased. Our results supported that FABP4 contributed to RIF via promoting inflammation and lipid metabolism, which should be considered as one new drug target to treat RIF.

Specific ablation of CD4+ T-cells promotes heart regeneration in juvenile mice

“…Additionally, S4 was a prominent subset that was enormously increased in the P8 (10.2%) compared to the P3 (0.3%) hearts (Table 1 ). In particular, there were a lot more P8 than P3 cells expressing genes that encoded for extracellular matrix proteins or secreted proteins associated with fibroblast activation and fibrosis such as S100a8 16 , Fabp4 17 , Sparc 18 , Mfap4 19 and Mfap5 20 ; or collagen proteins such as Col3a1 , Col1a1 , Col1a2 , Col4a1 and Col4a2 (Figure 4 E). In the cardiovascular system, FABP4 has been demonstrated to cause pressure overload-induced cardiac hypertrophy 21 ; and can be therapeutically targeted against severe atherosclerosis 22 .…”

GADD45α drives brown adipose tissue formation through upregulating PPARγ in mice

“…6a ), suggesting GADD45α interacts with PPARγ. To examine whether the interaction regulates the transcriptional activities of PPARγ, we performed a chromatin immunoprecipitation and luciferase reporter assay of FABP4, which is a downstream target of PPARγ and directly regulated by PPARγ 37 – 39 . The chromatin immunoprecipitation (ChIP) and luciferase reporter assays indicated that PPARγ directly bound to the promoter of FABP4 to enhance FABP4 gene transcription (Supplementary Fig.…”

“…Here, we demonstrated that GADD45α interacts with PPARγ and upregulates its transcriptional activity. The activated form of PPARγ is well-accepted to be upstream of FABP4, which is also known as adipocyte protein 2 (aP2) and is involved in the intracellular fatty acid transport and glucose and lipid homeostasis in mature adipocytes 37 – 39 . The promoter of FABP4 has been widely used in adipocyte-specific recombination in mice 60 , 61 .…”

Inhibition of Fatty Acid–Binding Protein 4 Attenuated Kidney Fibrosis by Mediating Macrophage-to-Myofibroblast Transition

“…Mechanistic studies demonstrated that FABP4-deficient macrophages suppressed inflammatory signaling, attenuated the activation of NF-κB pathway, and decreased endoplasmic reticulum stress (21). A recent study has reported that FABP4 deteriorated RIF via promoting NF-κB-mediated inflammation (14). It has been well recognized that inflammation is a key process leading to progressive renal fibrosis where intragraft macrophages, particularly activated macrophages, played crucial roles.…”