Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress
Small heat shock protein alteration provides a mechanism to reduce mesangial cell contractility in diabetes and oxidative stress
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DOI：
10.1046/j.1523-1755.2000.00866.x
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发表时间：
2000-02-01
影响因子：
19.6
通讯作者：
Muggli, EE
中科院分区：
文献类型：
--
作者：
Dunlop, ME;Muggli, EE
背景。小的热休克蛋白在许多组织中表达，当解离成小聚集体并以p38丝裂原活化蛋白激酶（p38MAPK）依赖的方式磷酸化时，被认为调节肌动蛋白丝动力学。在链脲佐菌素诱导的实验性糖尿病大鼠肾小球和暴露于自由基应激的离体肾小球中测定p38MAPK活性和小热休克蛋白25 （Hsp25）。系膜细胞的收缩反应性是通过血清诱导细胞包埋型胶原凝胶的收缩来测定的。在实验性糖尿病中，存在p38MAPK的激活，Hsp25分子聚集体的大小从大到小的同质寡聚物减小，以及Hsp25磷酸化的增加。在对照组肾小球中，自由基应激H2O2激活p38MAPK，并以浓度依赖的方式增加Hsp25。此外，H2O2降低了培养的系膜细胞的收缩性，同时Hsp25磷酸化增加，Hsp25聚集体大小减少。SB202190（一种咪唑衍生物的p38mapk细胞渗透性抑制剂）显著降低了这些作用。有人提出，糖尿病中氧源性自由基的产生可能与肾小球收缩反应性丧失和糖尿病早期的高滤过有关。该研究提供了通过Hsp25磷酸化改变系膜细胞收缩反应的机制，并可能是糖尿病和自由基应激下肾小球血流动力学异常的机制。
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 protein25 (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.