title: Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress.
abstract: BACKGROUND
  Small heat shock proteins are expressed in many tissues and are proposed to regulate actin filament dynamics when dissociated into small aggregates and phosphorylated in a p38 mitogen-activated protein kinase (p38MAPK)-dependent manner.
  
  
  METHODS
  p38MAPK activity and small heat shock protein-25 (Hsp25) were determined in glomeruli from rats with experimental diabetes induced by streptozotocin administration and in isolated glomeruli exposed to a free radical stress. Contractile responsiveness of mesangial cells was determined by the serum-induced contraction of cell-embedded type I collagen gels.
  
  
  RESULTS
  In experimental diabetes, there is an activation of p38MAPK, a decrease in the size of Hsp25 molecular aggregates, from large to small homo-oligomers, and an increase in the phosphorylation of Hsp25. In control glomeruli, a free radical stress, H2O2, activated p38MAPK and increased Hsp25 in a concentration-dependent manner. Additionally, H2O2 decreased the contractility of cultured mesangial cells concomitant with an increase in Hsp25 phosphorylation and a reduction in Hsp25 aggregate size. These effects were significantly reduced by SB202190, an imidazole-derivative cell-permeable inhibitor of p38MAPK.
  
  
  CONCLUSIONS
  It has been proposed that the generation of oxygen-derived free radicals in diabetes may be linked causally to a loss of glomerular contractile reactivity and thus hyperfiltration in the early stages of diabetes mellitus. This study provides a mechanism for alteration of mesangial cell contractile responsiveness through phosphorylation of Hsp25 and may be a mechanism underlying abnormalities in glomerular hemodynamics in diabetes and in the presence of free radical stress.
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. m.dunlop@medicine,unimelb.edu.au
authors.forename: M E
authors.initials: ME
authors.lastname: Dunlop
authors.forename: E E
authors.initials: EE
authors.lastname: Muggli
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D005920:Glomerular Mesangium / Q000201:enzymology* / Q000473:pathology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000032:analysis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005609:Free Radicals; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D009363:Neoplasm Proteins; D016877:Oxidants; D010761:Phosphorus Radioisotopes; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole