MOLECULAR MECHANISM OF MESANGIAL DYSFUNCTION IN DIABETES

肾小球滤过率增高，即肾小球高滤过，是糖尿病肾脏的主要异常之一，被认为与糖尿病肾病的未来发展有关。我们之前的研究表明，糖尿病肾小球对血管紧张素II的收缩反应性降低，这表明系膜细胞功能障碍在糖尿病肾小球高滤过中的重要性。本研究旨在阐明这种系膜细胞功能障碍的机制。得到了以下结果：在高糖条件下培养的系膜细胞中，anp诱导的cGMP积累增强。相比之下，血管紧张素II对anp诱导的cGMP积累的抑制作用减弱，细胞IP3对血管紧张素II的反应也减弱。蛋白激酶C （PKC）在高糖条件下被激活，PKC α和zeta易位。在高糖条件下培养的细胞中，PKC活性的抑制导致血管紧张素II作用降低的改善。这些结果表明，在高糖条件下培养的系膜细胞中，PKC活性的升高可能使血管紧张素II的作用脱敏，从而导致系膜细胞对血管紧张素II的收缩反应降低。因此，糖尿病状态下的肾小球系膜细胞可能有松弛的倾向，这种系膜细胞功能障碍有助于糖尿病肾小球高滤过的发生。

Increase in glomerular filtration rates, glomerular hyperfiltration, is one of the major abnormalities in diabetic kidneys and is considered to be related to future development of diabetic nephropathy. We have previously shown that the contractile responsiveness of diabetic glomeruli to angiotensin II is reduced indicating the importance of mesangial cell dysfunction in diabetic glomerular hyperfiltration. The present study was performed to clarify the mechanism of this mesangial cell dysfunction. The following results were obtained ;1. In mesangial cells cultured under high glucose conditions, ANP-induced cGMP accumulation was enhanced.2. In contrast, inhibitory effects of angiotensin II on ANP-induced cGMP accumulation was reduced and the response of cellular IP3 to angiotensin II was also reduced.3. Protein kinase C (PKC) was activated in cells cultured under high glucose conditions and the translocation of PKC alpha and zeta was observed.4. Inhibition of PKC activities resulted in an amelioration of the reduction of angiotensin II action in cells cultured under high glucose conditions.These results indicate that, in mesangial cells cultured under high glucose conditions, and elevation of PKC activities may desensitize the action of angiotensin II and thus result in decreased contractile responsiveness of mesangial cells to angiotensin II.Therefore, mesangial cells in diabetic state may have a tendency to relax and this mesangial cell dysfunction, contributes to the development of glomerular hyperfiltration in diabetes.