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

Alicia Jenkins, V Velarde, R L Klein, K C Joyce, K D Phillips, R K Mayfield, T J Lyons, A A Jaffa

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Glycation and/or oxidation of LDL may promote diabetic nephropathy. The mitogen-activated protein kinase (MAPK) cascade, which includes extracellular signal-regulated protein kinases (ERKs), modulates cell function. Therefore, we examined the effects of LDL on ERK phosphorylation in cultured rat mesangial cells. In cells exposed to 100 microg/ml native LDL or LDL modified by glycation, and/or mild or marked (copper-mediated) oxidation, ERK activation peaked at 5 min. Five minutes of exposure to 10-100 microg/ml native or modified LDL produced a concentration-dependent (up to sevenfold) increase in ERK activity. Also, 10 microg/ml native LDL and mildly modified LDL (glycated and/or mildly oxidized) produced significantly greater ERK activation than that induced by copper-oxidized LDL +/- glycation (P <0.05). Pretreatment of cells with Src kinase and MAPK kinase inhibitors blocked ERK activation by 50-80% (P <0.05). Native and mildly modified LDL, which are recognized by the native LDL receptor, induced a transient spike of intracellular calcium. Copper-oxidized (+/- glycation) LDL, recognized by the scavenger receptor, induced a sustained rise in intracellular calcium. The intracellular calcium chelator (EGTA/AM) further increased ERK activation by native and mildly modified LDL (P <0.05). These findings demonstrate that native and modified LDL activate ERKs 1 and 2, an early mitogenic signal, in mesangial cells and provide evidence for a potential link between modified LDL and the development of glomerular injury in diabetes.
Original languageEnglish
Pages (from-to)2160-9
Number of pages10
JournalDiabetes
Volume49
Issue number12
Publication statusPublished - Dec 2000

Keywords

  • Animals
  • Calcium
  • Cells, Cultured
  • Enzyme Activation
  • Glomerular Mesangium
  • Glycosylation
  • Humans
  • Lipoproteins, LDL
  • Male
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Osmolar Concentration
  • Oxidation-Reduction
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • src-Family Kinases

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