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Anti-proliferative actions of T-type calcium channel inhibition in Thy1 nephritis

Andrea Cove-Smith1, Christopher J Mulgrew, Olena Rudyk

  • 1Department of Renal Medicine, King's College London, London, United Kingdom. andrea.cove-smith@kcl.ac.uk

The American Journal of Pathology
|June 11, 2013
PubMed

Insights

TH1177, a T-type calcium channel (TCC) inhibitor, significantly reduced mesangial cell proliferation in vitro and in vivo. This suggests TCC inhibition may be a viable strategy for treating progressive glomerular diseases characterized by aberrant cell growth.

Area of Science:

  • Nephrology
  • Cell Biology
  • Pharmacology

Background:

  • Aberrant mesangial cell (MC) proliferation is a hallmark of progressive glomerular diseases.
  • T-type calcium channels (TCCs) are implicated in cellular proliferation.
  • TH1177 is a small molecule inhibitor of TCCs.

Purpose of the Study:

  • To investigate the effect of TH1177 on MC proliferation in vitro and in vivo.
  • To determine if TCC inhibition can ameliorate glomerular injury and MC overgrowth in a rat model of nephritis.

Main Methods:

  • In vitro studies utilized microculture tetrazolium assays and bromodeoxyuridine incorporation to assess rat MC proliferation.
  • In vivo studies involved treating rats with Thy1 nephritis with TH1177 or vehicle, followed by blinded assessment of glomerular injury, cell number, and markers of proliferation (Ki-67, pERK).
  • Quantitative real-time PCR was used to analyze TCC isoform expression in healthy and diseased kidney tissue.

Main Results:

  • TCC blockade significantly reduced rat MC proliferation in vitro, while L-type calcium channel inhibition had no effect.
  • TH1177 treatment in Thy1 nephritis model significantly reduced glomerular injury and glomerular cell number by 49%.
  • TH1177 administration also led to significant reductions in Ki-67 and pERK positive cells per glomerulus.

Conclusions:

  • TH1177 effectively inhibits mesangial cell proliferation both in vitro and in vivo.
  • These findings support the therapeutic potential of TCC inhibition for managing proliferative responses in glomerular diseases.
  • Targeting TCCs offers a promising strategy for future research and treatment of kidney injury.

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