肌醇磷脂代谢异常导致糖尿病视网膜病变时毛细血管周细胞消失

在高浓度葡萄糖条件下(模拟糖尿病条件)培养视网膜毛细血管周细胞,由于调控细胞增殖的第二信使——肌醇磷脂代谢产物减少,使周细胞增殖活力降低。在高葡萄糖条件下,周细胞内肌醇水平下降、山梨醇通路被激活;外加肌醇或阻断山梨醇通路则可使异常的肌醇磷脂代谢得到不同程度的纠正,周细胞增殖活力亦随之回升。提示外加肌醇和阻断山梨醇通路是防止糖尿病周细胞衰亡的有效体外治疗。

Abnormal Inositoi Phosphoiipid Metabolism as a Main Factor Causing Pericyte Drop-out in Diabetic Retinopathy

The biochemical basis of pericyte loss in early diabetic retinopathy is still an open question. In studies on the mechanism by which retinal peri-cytes degenerate, we first established a bovine retinal capillary pericyte (BRCP) cell line. Subcultured BRCP grown in high (10-40mmol/L) glucose media were used as an experimental model. We found that high concentrations of glucose suppress the mitotic rate and cell birth rate of cultured BRCP. High concentrations of glucose inhibit myo-inositol transport and result in decreased intracellular myo-inositol content. This inhibition can be partially reversed by sorbinil, an aldose reductase inhibitor (ARI). Myo-inositol is a precursor of inositol phospholipids (IPLs), whose metabolism is responsible for a number of signal transduction processes. Phosphoinositidase (Plase) cleaves the phos-phodiester bond of phosphotidylinositol 4,5 diphosphate (PIP2) to produce two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). Further experiments showed that IP3 and DG synergistically activate BRCP proliferation in vitro. High concentrations of glucose altered the formation of both IPLs and inositol phosphate esters (IPEs) in an organ culture of retinal micro-vessels. This alteration can be reversed by adding either high concentrations of myo-inositol or ARI to the medium. Plase activity was attenuated to 82% or 55% when glucose in the growth medium was increased from 5 to 15 or 30 mmol/L, respectively. When IPLs from BRCP were analyzed by HPLC and TLC, we observed the reduction of three IPLs, including the substrate of Plase, PIP2. The reduced levels of IPLs were restored by adding either free myo-inositol or ARI to the high-glucose medium. These findings suggest that the alteration in IPL metabolism in BRCP may be related to insufficient myo-inositol or to an activated sorbitol pathway under high glucose conditions. The supplementation of either inositol or ARIs may be used as in vitro therapy for the treatment of "diabetic pericytes".