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

Abstract

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. 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. 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. 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.