Dataset Information

?klotho is essential for the anti-endothelial mesenchymal transition effects of N-acetyl-seryl-aspartyl-lysyl-proline.

ABSTRACT: Endothelial-mesenchymal transition (EndMT) has emerged as an essential bioprocess responsible for the development of organ fibrosis. We have previously reported that fibroblast growth factor receptor 1 (FGFR1) is involved in the anti-EndMT effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). FGFR1 is expressed on the cell membrane and performs its biological function through interaction with co-receptors, including ?klotho (KLB). However, it remains unknown whether KLB is involved in the anti-EndMT effects of AcSDKP. Here, we demonstrated that AcSDKP increased KLB expression in an FGFR1-dependent manner and that KLB deficiency induced AcSDKP-resistant EndMT via the induction of the mitogen-activated protein kinase (MAPK) pathway. In cultured endothelial cells, AcSDKP increased KLB protein level in an FGFR1-dependent manner through induction of the FGFR1-KLB complex. KLB suppression by small interfering RNA transfection did not affect FGFR1 levels and resulted in the induction of EndMT. In contrast to the EndMT observed under FGFR1 deficiency, the EndMT induced by KLB suppression was not accompanied by the induction of Smad3 phosphorylation; instead, KLB-deficient cells exhibited induced activation of the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK pathways. Treatment with the specific MEK inhibitor U0126 diminished KLB deficiency-induced EndMT. Consistent with this finding, AcSDKP did not suppress either EndMT or MEK/ERK activation induced by KLB deficiency. Application of either FGF19 or FGF21 synergistically augmented the anti-EndMT effects of AcSDKP. Taken together, these results indicate that endogenous peptide AcSDKP exerts its activity through induction of the FGFR1-KLB complex in vascular endothelial cells.

SUBMITTER: Gao R

PROVIDER: S-EPMC6487725 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

βklotho is essential for the anti-endothelial mesenchymal transition effects of N-acetyl-seryl-aspartyl-lysyl-proline.

Gao Rongfen R Kanasaki Keizo K Li Jinpeng J Kitada Munehiro M Okazaki Toshiro T Koya Daisuke D

FEBS open bio 20190422 5

Endothelial-mesenchymal transition (EndMT) has emerged as an essential bioprocess responsible for the development of organ fibrosis. We have previously reported that fibroblast growth factor receptor 1 (FGFR1) is involved in the anti-EndMT effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). FGFR1 is expressed on the cell membrane and performs its biological function through interaction with co-receptors, including βklotho (KLB). However, it remains unknown whether KLB is involved in the an ...[more]

PMID: 30972974

Similar Datasets

Project description:Background and Purpose- Stroke is a leading cause of disability worldwide, mainly affecting the elderly. However, preclinical studies in aged ischemic animals are limited. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a naturally occurring tetrapeptide with vascular-protective properties. The present study investigated the effect of AcSDKP on tPA (tissue-type plasminogen activator)-induced thrombolysis in aged rats after ischemic stroke. Methods- Aged male rats (18 months) were subjected to embolic middle cerebral artery occlusion. Rats subjected to 4 hours of middle cerebral artery occlusion were randomized into the following groups: (1) AcSDKP; (2) tPA; (3) AcSDKP in combination with tPA; and (4) saline. Neurological deficits, cerebral microvascular patency and integrity, and infarction were examined at 1 day and 7 days after middle cerebral artery occlusion. In vitro experiments were performed to examine the effect of AcSDKP on aged cerebral endothelial cell permeability. Results- Compared with saline, AcSDKP, or tPA as monotherapy did not have any therapeutic effects, whereas AcSDKP in combination with tPA significantly reduced cerebral tissue infarction and improved neurological outcome without increasing cerebral hemorrhage. Concurrently, the combination treatment significantly augmented microvascular perfusion and reduced thrombosis and blood-brain barrier leakage. In vitro, compared with cerebral endothelial cells from ischemic adult rats, the endothelial cells from ischemic aged rats exhibited significantly increased leakage. AcSDKP suppressed tPA-induced aged endothelial cell leakage and reduced expression of ICAM-1 (intercellular adhesion molecule 1) and NF (nuclear factor)-κB. Conclusions- The present study provides evidence for the therapeutic efficacy of AcSDKP in combination tPA for the treatment of embolic stroke in aged rats at 4 hours after stroke onset. AcSDKP likely acts on cerebral endothelial cells to enhance the benefits of tPA by increasing tissue perfusion and augmenting the integrity of the blood-brain barrier. Visual Overview- An online visual overview is available for this article.

Dataset Information

?klotho is essential for the anti-endothelial mesenchymal transition effects of N-acetyl-seryl-aspartyl-lysyl-proline.

Publications

βklotho is essential for the anti-endothelial mesenchymal transition effects of N-acetyl-seryl-aspartyl-lysyl-proline.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets