噻唑烷二酮类药物对糖尿病肾病的直接作用及其机制

近年的研究显示 ,噻唑烷二酮类药物 (TZD)具有不依赖于胰岛素增敏作用的肾直接保护作用 ,在未降低糖尿病大鼠高血糖水平的情况下 ,TZD可减少清蛋白尿 ,抑制肾小球系膜肥大及细胞外基质 (ECM)增生。其可能的作用机制是 :在高血糖状态下 ,TZD通过激活肾小球中二酰基甘油激酶 (DGK) ,抑制二酰基甘油 (DAG) 蛋白激酶C(PKC) 细胞信号调节激酶 (ERK)通路活性而改善肾小球高滤过状态、抑制ECM蛋白的过度产生。也有研究认为 ,TZD与改善硫酸乙酰肝素原多糖 (HSPG)合成及硫酸化、从而抑制肾小球基膜 (GBM)外疏松层的阴离子位点有关。此外 ,TZD可能通过调节肾小球系膜细胞的表型转化达到肾保护作用。

Direct effects and mechanisms of thiazolidinediones on oiabetic nephropathy

Recent studies have shown that thiazolidinediones (TZD) have preventive effects on kidney in diabetes through a novel mechanism independent of its insulin-sensitizing action. TZD are able to prevent diabetic albuminuria, glomerular hypertrophy and increase in extracellular matrix proteins in the glomeruli of diabetic rats, without changing blood glucose levels. The mechanism may be under high glucose conditions, TZD enhance the activities of DAG kinase, inhibit the activation of diacylglycerol-protein kinase C-extracellular signal-regulated kinase (DAG-PKC-ERK)pathway, thus ameliorate the diabetic glomerular hyperfiltration and an overexpression of extracellular matrix proteins. Some studies suggested that it may be related to the action of ameliorating the synthesis of heparan sulfate proteoglycans(HSPG), and then suppressing the loss of anionic sites of glomerular basement membranes (GBM) of diabetic rats. Also the modulating of the phenotypic change of the mesangial cells by TZD has been reported.