Haneda M, Araki S, Togawa M, Sugimoto T, Isono M, Kikkawa R
Third Department of Medicine, Shiga University of Medical Science, Japan.
Diabetes. 1997 May;46(5):847-53. doi: 10.2337/diab.46.5.847.
The activation of protein kinase C (PKC) found in diabetic glomeruli and glomerular mesangial cells cultured under high glucose conditions has been proposed to contribute to the development of diabetic nephropathy. However, the abnormalities distal to PKC have not been fully elucidated yet. Herein, we provide the evidence that mitogen-activated protein kinase (MAPK) cascade, an important kinase cascade downstream to PKC and an activator of cytosolic phospholipase A2 (cPLA2) by direct phosphorylation, is activated in glomeruli isolated from streptozotocin-induced diabetic rats. MAPK cascade was also activated in glomerular mesangial cells cultured under high glucose (27.8 mmol/l) conditions for 5 days, and the activation of MAPK cascade was inhibited by treating the cells with calphostin C, an inhibitor of PKC. Furthermore, the activities of cPLA2 also increased in cells cultured under the same conditions and this activation was inhibited by both calphostin C and PD 098059, an inhibitor of MEK (MAPK or extracellular signal-regulated kinase [ERK] kinase). These results indicate that MAPK cascade is activated in glomeruli and mesangial cells under the diabetic state possibly through the activation of PKC. Activated MAPK, in turn, may induce various functional changes of mesangial cells at least through the activation of cPLA2 and contribute to the development of diabetic nephropathy.
糖尿病肾小球及在高糖条件下培养的肾小球系膜细胞中发现的蛋白激酶C（PKC）激活，被认为与糖尿病肾病的发展有关。然而，PKC下游的异常情况尚未完全阐明。在此，我们提供证据表明，丝裂原活化蛋白激酶（MAPK）级联反应，这是PKC下游的一个重要激酶级联反应，且通过直接磷酸化作用作为胞质磷脂酶A2（cPLA2）的激活剂，在从链脲佐菌素诱导的糖尿病大鼠分离出的肾小球中被激活。在高糖（27.8 mmol/l）条件下培养5天的肾小球系膜细胞中，MAPK级联反应也被激活，并且用PKC抑制剂钙泊三醇C处理细胞可抑制MAPK级联反应的激活。此外，在相同条件下培养的细胞中，cPLA2的活性也增加，并且这种激活被钙泊三醇C和MEK（MAPK或细胞外信号调节激酶[ERK]激酶）抑制剂PD 098059所抑制。这些结果表明，在糖尿病状态下，MAPK级联反应可能通过PKC的激活在肾小球和系膜细胞中被激活。反过来，活化的MAPK可能至少通过激活cPLA2诱导系膜细胞的各种功能变化，并促进糖尿病肾病的发展。
