Kikkawa Ryuichi, Koya Daisuke, Haneda Masakazu
Third Department of Medicine, Shiga University of Medical Science, Shiga, Japan.
Am J Kidney Dis. 2003 Mar;41(3 Suppl 1):S19-21. doi: 10.1053/ajkd.2003.50077.
Diabetic nephropathy, a kidney disease caused by diabetes, is the most devastating and money-consuming complication in patients with diabetes throughout the world. The cardinal lesion of diabetic nephropathy resides in renal glomeruli and is called diabetic glomerulosclerosis. Hyperglycemia is responsible for the development and progression of diabetic nephropathy through metabolic derangements, including increased oxidative stress, renal polyol formation, activation of protein kinase C (PKC)-mitogen-activated protein kinases (MAPKs), and accumulation of advanced glycation end products, as well as such hemodynamic factors as systemic hypertension and increased intraglomerular pressure.
We examined whether inhibition of the PKC-MAPK pathway could inhibit functional and pathological abnormalities in glomeruli from diabetic animal models and cultured mesangial cells exposed to high glucose condition and/or mechanical stretch.
Direct inhibition of PKC by PKC beta inhibitor prevented albuminuria and mesangial expansion in db/db mice, a model of type 2 diabetes. We also found that inhibition of MAPK by PD98059, an inhibitor of MAPK, or mitogen-activated extracellular regulated protein kinase kinase prevented enhancement of activated protein-1 (AP-1) DNA binding activity and fibronectin expression in cultured mesangial cells exposed to mechanical stretch in an in vivo model of glomerular hypertension.
These findings highlight the important role of PKC-MAPK pathway activation in mediating the development and progression of diabetic nephropathy.
糖尿病肾病是一种由糖尿病引起的肾脏疾病，是全球糖尿病患者中最具破坏性且耗费金钱的并发症。糖尿病肾病的主要病变位于肾小球，称为糖尿病性肾小球硬化症。高血糖通过代谢紊乱导致糖尿病肾病的发生和发展，这些代谢紊乱包括氧化应激增加、肾脏多元醇生成、蛋白激酶C（PKC）-丝裂原活化蛋白激酶（MAPK）激活、晚期糖基化终产物积累，以及诸如系统性高血压和肾小球内压升高等血流动力学因素。
我们研究了抑制PKC-MAPK通路是否能抑制糖尿病动物模型肾小球以及暴露于高糖条件和/或机械牵张的培养系膜细胞中的功能和病理异常。
PKCβ抑制剂直接抑制PKC可预防2型糖尿病模型db/db小鼠的蛋白尿和系膜扩张。我们还发现，在肾小球高血压的体内模型中，MAPK抑制剂PD98059或丝裂原活化细胞外调节蛋白激酶激酶抑制MAPK可防止暴露于机械牵张的培养系膜细胞中活化蛋白-1（AP-1）DNA结合活性增强和纤连蛋白表达增加。
这些发现突出了PKC-MAPK通路激活在介导糖尿病肾病发生和发展中的重要作用。
