Recombinant FGF21 Protects Against Blood-Brain Barrier Leakage Through Nrf2 Upregulation in Type 2 Diabetes Mice

Abstract

Blood-brain barrier (BBB) damage is a characteristic feature of diabetes mellitus pathology and plays significant roles in diabetes-associated neurological disorders. However, effective treatments for diabetes targeting BBB damage are yet to be developed. Fibroblast growth factor 21 (FGF21) is a potent regulator of lipid and glucose metabolism. In this study, we tested the hypothesis that recombinant FGF21 (rFGF21) administration may reduce type 2 diabetes (T2D)-induced BBB disruption via NF-E2-related factor-2 (Nrf2) upregulation. Our experimental results show that rFGF21 treatment significantly ameliorated BBB permeability and preserved junction protein expression in db/db mice in vivo. This protective effect was further confirmed by ameliorated transendothelial permeability and junction protein loss by rFGF21 under hyperglycemia and IL1β (HG-IL1β) condition in cultured human brain microvascular endothelial cells (HBMEC) in vitro. We further reveal that rFGF21 can activate FGF receptor 1 (FGFR1) that increases its binding with Kelch ECH-associating protein 1 (Keap1), a repressor of Nrf2, thereby reducing Keap1-Nrf2 interaction leading to Nrf2 release. These data suggest that rFGF21 administration may decrease T2D-induced BBB permeability, at least in part via FGFR1-Keap1-Nrf2 activation pathway. This study may provide an impetus for development of therapeutics targeting BBB damage in diabetes.

Panax notoginseng saponins suppress lipopolysaccharide‐induced barrier disruption and monocyte adhesion on bEnd.3 cells via the opposite modulation of Nrf2 antioxidant and NF‐κB inflammatory pathways

“…Upon stimulation with external stimuli, Nrf2 dissociates from the complex, translocate to the nucleus, binds to the antioxidant response element, and subsequently activates transcription aimed at cytoprotective and antioxidant factors, including HO‐1 (Loboda et al, ). Indeed, Nrf2 activation has been demonstrated to contribute to the upregulation of TJs expression and protection of BBB integrity (Yu et al, ). In addition, saponins in P. notoginseng are reported to motivate endogenous cytoprotective mechanism against oxidative injury in an Nrf2‐dependent manner (Huang et al, ; Zhou, Tang, Keep, Ma, & Xiang, ).…”

“…Actually, in unstimulated cells, Nrf2 is normally present in the cytoplasm, along (Loboda et al, 2016). Indeed, Nrf2 activation has been demonstrated to contribute to the upregulation of TJs expression and protection of BBB integrity (Yu et al, 2019). In addition, saponins in P. notoginseng are reported to motivate endogenous cytoprotective mechanism against oxidative injury in an Nrf2-dependent manner (Huang et al, 2014;Zhou, Tang, Keep, Ma, & Xiang, 2014).…”

“…Nuclear factor‐erythroid 2‐related factor 2 (Nrf2) is a transcription factor for the regulation of antioxidant‐responsive genes such as heme oxygenase‐1 (HO‐1), which plays an active role in the resistance to intracellular ROS (Loboda, Damulewicz, Pyza, Jozkowicz, & Dulak, ). Indeed, the activation of Nrf2 after cerebral injury has been shown to alleviate the TJs loss and BBB disruption, indicating its protective role in BBB integrity (Yu et al, ). Nuclear factor‐kappa B (NF‐κB) is a family of stress‐responsive transcription factors relating to the inflammatory response, and suppression of NF‐κB may also benefit the BBB integrity (Afonina, Zhong, Karin, & Beyaert, ; Zhang et al, ).…”

FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARγ Activation

“…In this study, we tested our hypothesis that poststroke administration of rFGF21 is protective against early BBB damage in T2DM mice via FGFR1-mediated elevation of cerebrovascular PPARγ activity. Two sets of experiments were designed as followed: in vivo study was performed using a focal stroke model in T2DM mice, treated with or without rFGF21 as we previously described [10], and an in vitro study was conducted using cultured human brain microvascular endothelial cells (HBMECs), insulted by a well-established hyperglycemia plus interleukin (IL)-1β exposure model to mimic in vivo situation of diabetic stroke as we previously described [15].…”

Heparin‐poloxamer hydrogel‐encapsulated rhFGF21 enhances wound healing in diabetic mice

“…FGF21, a member of the FGF family, has been reported to regulate glycolipid metabolism, maintain energy balance, exert anti-inflammatory and antioxidation effects (36), protect the blood-brain barrier from traumatic brain injury, protect against blood-brain barrier leakage in T2DM (37,38), and facilitate remyelination of injured peripheral nerves and functional recovery. However, to the best of our knowledge, no research has shown that FGF21 can repair skin wounds.…”