Extracellular calcium-sensing receptor mediated signalling is involved in human vascular smooth muscle cell...

Area of Science:

• Vascular Biology
• Cell Signaling
• Chronic Kidney Disease Pathophysiology

Background:

• Vascular calcification is a significant complication in chronic kidney disease (CKD).
• The calcium-sensing receptor (CaSR) is implicated in vascular calcification.
• The precise role of CaSR in vascular smooth muscle cell (SMC) behavior requires further elucidation.

Purpose of the Study:

• To investigate the role of CaSR in regulating human aortic smooth muscle cell (HAoSMC) proliferation and apoptosis.
• To elucidate the signaling pathways, specifically MEK1/ERK1,2 and phospholipase C (PLC), involved in CaSR-mediated effects on HAoSMCs.

Main Methods:

• HAoSMCs were treated with CaSR agonist (neomycin) and inhibitors (PD98059, U73122).
• ERK1,2 phosphorylation and inositol triphosphate (IP3) production were measured to assess signaling pathway activation.
• CaSR knockdown was performed using siRNA to confirm CaSR-dependent signaling.
• Cell proliferation and apoptosis assays were conducted to evaluate cellular responses.

Main Results:

• Neomycin (CaSR agonist) significantly increased ERK1,2 phosphorylation via the MEK1/ERK1,2 and PLC pathways.
• CaSR knockdown attenuated neomycin-induced ERK1,2 phosphorylation and IP3 production.
• Neomycin stimulated HAoSMC proliferation, an effect reduced by CaSR knockdown and pathway inhibitors.
• Neomycin did not affect apoptosis, whereas U73122 (PLC inhibitor) increased apoptosis, an effect exacerbated by CaSR knockdown.

Conclusions:

• CaSR stimulation activates MEK1/ERK1,2 and PLC signaling pathways, leading to increased SMC proliferation.
• CaSR-mediated PLC activation plays a critical role in SMC survival and protection against apoptosis.
• Targeting CaSR signaling may offer therapeutic potential for managing vascular complications in CKD.