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Native and modified LDL activate extracellular signal-regulated kinases in mesangial cells

A J Jenkins1, V Velarde, R L Klein

  • 1Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.

Diabetes
|December 16, 2000
PubMed

Insights

Modified LDL activates extracellular signal-regulated kinases (ERKs) in kidney cells, potentially linking to diabetic kidney disease. This early mitogenic signal involves intracellular calcium changes and receptor interactions.

Area of Science:

  • Nephrology
  • Cell Biology
  • Diabetology

Background:

  • Diabetic nephropathy is a potential complication of LDL modification.
  • Mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated protein kinases (ERKs), regulate cellular functions.
  • The role of LDL in modulating mesangial cell ERK activity in diabetes is not fully understood.

Purpose of the Study:

  • To investigate the effects of native and modified low-density lipoprotein (LDL) on ERK phosphorylation in cultured rat mesangial cells.
  • To explore the mechanisms underlying LDL-induced ERK activation, including the role of intracellular calcium and specific receptors.

Main Methods:

  • Cultured rat mesangial cells were exposed to native LDL and LDL modified by glycation and/or oxidation.
  • ERK activation was measured via phosphorylation.
  • Inhibitors of Src kinase and MAPK kinase were used to block ERK activation.
  • Intracellular calcium levels were monitored using calcium chelators.

Main Results:

  • Native and modified LDL induced a concentration- and time-dependent increase in ERK activation.
  • Mildly modified LDL showed greater ERK activation compared to heavily oxidized LDL.
  • Inhibitors significantly blocked LDL-induced ERK activation.
  • Different LDL modifications led to distinct patterns of intracellular calcium changes.
  • Calcium chelation enhanced ERK activation by native and mildly modified LDL.

Conclusions:

  • Native and modified LDL activate ERKs 1 and 2 in mesangial cells, representing an early mitogenic signal.
  • These findings suggest a potential link between modified LDL and the pathogenesis of glomerular injury in diabetic nephropathy.
  • The study highlights the differential roles of LDL receptors and intracellular calcium signaling in mediating these effects.

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