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Published on: July 16, 2013
Inhibition of human mesangial cell proliferation by targeting T-type calcium channels
Christopher J Mulgrew1, Andrea Cove-Smith, Linda M McLatchie
1Department of Renal Medicine, King's College London, London, UK.
Background:
Aberrant glomerular mesangial cell (MC) proliferation is a common finding in renal diseases. T-type calcium channels (T-CaCN) play an important role in the proliferation of a number of cell types, including vascular smooth muscle cells. The hypothesis that T-CaCN may play a role in the proliferation of human MC was investigated.
Methods:
The presence of T-CaCN in primary cultures of human MC was examined using voltage clamping and by RT-PCR. The effect of calcium channel inhibitors, and of siRNA directed against the Cav3.2 T-CaCN isoform, on MC proliferation was assessed using the microculture tetrazolium assay and nuclear BrdU incorporation.
Results:
Human MC express only the Cav3.2 T-CaCN isoform. Co-incubation of MC with a T-CaCN inhibitor (mibefradil, TH1177 or Ni(2+)) results in a concentration-dependent attenuation of proliferation. This effect cannot be attributed to direct drug-induced cytotoxicity or apoptosis and is not seen with verapamil, an L-type channel blocker. Transfection of MC with siRNA results in knockdown of T-CaCN Cav3.2 mRNA and a clear attenuation of MC proliferation.
Conclusions:
These results demonstrate for the first time an important role for T-CaCN in human MC proliferation. This could potentially lead to a novel therapy in the treatment of proliferative renal diseases.
Insights
T-type calcium channels (T-CaCN) are crucial for human mesangial cell proliferation in kidney diseases. Inhibiting these channels significantly reduces cell growth, suggesting a new therapeutic target for renal disorders.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Aberrant glomerular mesangial cell (MC) proliferation is characteristic of renal diseases.
- T-type calcium channels (T-CaCN) are implicated in the proliferation of various cell types, including vascular smooth muscle cells.
Purpose of the Study:
- To investigate the role of T-type calcium channels (T-CaCN) in the proliferation of human mesangial cells (MC).
Main Methods:
- Examined T-CaCN presence in human MC cultures via voltage clamping and RT-PCR.
- Assessed the impact of T-CaCN inhibitors and Cav3.2 isoform-specific siRNA on MC proliferation using tetrazolium assays and BrdU incorporation.
Main Results:
- Human MC exclusively express the Cav3.2 T-CaCN isoform.
- T-CaCN inhibitors (mibefradil, TH1177, Ni2+) demonstrated a concentration-dependent reduction in MC proliferation without inducing cytotoxicity or apoptosis.
- Cav3.2 siRNA transfection effectively reduced T-CaCN Cav3.2 mRNA levels and MC proliferation.
Conclusions:
- Established a significant role for T-type calcium channels (T-CaCN) in human MC proliferation.
- Identified T-CaCN as a potential therapeutic target for proliferative renal diseases.
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