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S1PR2 antagonist ameliorate high glucose-induced fission and dysfunction of mitochondria in HRGECs via regulating ROCK1
- Source :
- BMC Nephrology, Vol 20, Iss 1, Pp 1-8 (2019), BMC Nephrology
- Publication Year :
- 2019
- Publisher :
- BMC, 2019.
-
Abstract
- Aims Sphingosine-1-phosphate receptor 2 (S1PR2) is a G-protein-coupled receptor that regulates sphingosine-1-phosphate-triggered cellular response. However, the role of S1PR2 in diabetes-induced glomerular endothelial cell dysfunction remains unclear. This study aims to investigate the effect of S1PR2 blockade on the morphology and function of mitochondria in human renal glomerular endothelial cells (HRGECs). Methods HRGECs were pretreated with a S1PR2 antagonist (JTE-013) or a Rho-associated coiled coil-containing protein kinase 1 (ROCK1) inhibitor (Y27632) for 30 min and then cultured with normal glucose (5.5 mM) or high glucose (30 mM) for 72 h. The protein expression levels of RhoA, ROCK1, and Dynmin-related protein-1(Drp1) were evaluated by immunoblotting; mitochondrial morphology was observed by electron microscopy; intracellular levels of ATP, ROS, and Ca2+ were measured by ATPlite, DCF-DA, and Rhod-2 AM assays, respectively. Additionally, the permeability, apoptosis, and migration of cells were determined to evaluate the effects of S1PR2 and ROCK1 inhibition on high glucose-induced endothelial dysfunction. Results High glucose induced mitochondrial fission and dysfunction, indicated by increased mitochondrial fragmentation, ROS generation, and calcium overload but decreased ATP production. High glucose also induced endothelial cell dysfunction, indicated by increased permeability and apoptosis but decreased migration. However, inhibition of either S1PR2 or ROCK1 almost completely blocked these high glucose-mediated cellular responses. Furthermore, inhibiting S1PR2 resulted in the deceased expression of RhoA, ROCK1, and Drp1 while inhibiting ROCK1 led to the downregulated expression of Drp1. Conclusions S1PR2 antagonist modulates the morphology and function of mitochondria in HRGECs via the positive regulation of the RhoA/ROCK1/Drp1 signaling pathway, suggesting that the S1PR2/ROCK1 pathway may play a crucial role in high glucose milieu. Electronic supplementary material The online version of this article (10.1186/s12882-019-1323-0) contains supplementary material, which is available to authorized users.
- Subjects :
- Blood Glucose
medicine.medical_specialty
RHOA
Pyridines
Kidney Glomerulus
030232 urology & nephrology
030204 cardiovascular system & hematology
Mitochondrion
lcsh:RC870-923
03 medical and health sciences
0302 clinical medicine
Endothelial cell
Internal medicine
Medicine
Humans
ROCK1
Diabetic Nephropathies
Endothelial dysfunction
Enzyme Inhibitors
Sphingosine-1-phosphate receptor 2
Sphingosine-1-Phosphate Receptors
Cells, Cultured
rho-Associated Kinases
biology
business.industry
Diabetes
Endothelial Cells
medicine.disease
lcsh:Diseases of the genitourinary system. Urology
Amides
Cell biology
Mitochondria
Endothelial stem cell
Nephrology
Apoptosis
biology.protein
Pyrazoles
Mitochondrial fission
Signal transduction
business
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14712369
- Volume :
- 20
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- BMC Nephrology
- Accession number :
- edsair.doi.dedup.....025f11cca84b1dfe3061de53df885625