Nishio Toshiki, Haneda Masakazu, Koya Daisuke, Inoki Ken, Maeda Shiro, Kikkawa Ryuichi
Third Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Eur J Pharmacol. 2002 Feb 22;437(3):113-22. doi: 10.1016/s0014-2999(01)01559-x.
Glomerular hypertension is proposed to play an important role in the progression of various glomerular diseases. Glomerular mesangial cells are considered to be exposed to the stretch stress due to glomerular hypertension and are found to produce the excess amount of extracellular matrix (ECM) proteins including fibronectin when exposed to the mechanical stretch. Herein, we provide the evidence that cAMP-generating agents inhibit the stretch-induced overexpression of fibronectin through the inhibition of the stretch-induced activation of mitogen-activated protein kinases (MAPKs) in protein kinase-A-dependent manner. We also found that the mechanical stretch enhanced the binding of nuclear extracts to activator protein-1 (AP-1)-like sequences in the promoter region of rat fibronectin gene and this enhancement was also prevented by the cAMP-generating agent. These results indicate that the agents, which activate cAMP/protein kinase-A axis, may work protectively against the injury from glomerular hypertension in mesangial cells.
肾小球高血压被认为在各种肾小球疾病的进展中起重要作用。肾小球系膜细胞被认为由于肾小球高血压而受到拉伸应力，并且发现当暴露于机械拉伸时会产生过量的细胞外基质（ECM）蛋白，包括纤连蛋白。在此，我们提供证据表明，产生cAMP的药物通过以蛋白激酶A依赖的方式抑制丝裂原活化蛋白激酶（MAPK）的拉伸诱导激活，从而抑制拉伸诱导的纤连蛋白过表达。我们还发现机械拉伸增强了核提取物与大鼠纤连蛋白基因启动子区域中激活蛋白-1（AP-1）样序列的结合，并且这种增强也被产生cAMP的药物所阻止。这些结果表明，激活cAMP/蛋白激酶A轴的药物可能对系膜细胞中肾小球高血压引起的损伤起保护作用。
