Abstract
Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood–brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin–treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte–thrombin interaction may play a key role in causing BBB dysfunction in obesity-associated diabetes and represent a therapeutic target for its CNS complications.
Highlights
The increasing prevalence of type 2 diabetes represents a major global health issue because of the numerous and often serious complications associated with it [1], including nephropathy, retinopathy and neuropathy [2]
(5) Thrombin treatment of brain pericytes caused fragmented immunostaining for zona occludens-1 (ZO-1) at the intercellular borders of rat brain microvascular endothelial cells (RBECs) and decreased ZO-1 and occludin protein levels in RBECs. (6) Thrombin stimulated brain pericytes to express pro-inflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)
high-fat diet (HFD)-feeding for 2 weeks (2W) and 8 weeks (8W) resulted in increased weight gain and impaired glucose tolerance was evident in mice fed a HFD for 8W but not 2W
Summary
The increasing prevalence of type 2 diabetes represents a major global health issue because of the numerous and often serious complications associated with it [1], including nephropathy, retinopathy and neuropathy [2]. Loss of pericytes causes microvascular diabetic complications; diabetic-induced albuminuria and diabetic retinopathy likely occur due to impaired podocyte [14, 15] and retinal pericyte [16, 17] function, respectively. In addition to these peripheral pathologies, loss of brain pericytes has been proposed to occur in diabetes, and a recent study reported loss of pericytes in the brain of diabetic mice [18]
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