Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress.

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.