Imai Goro, Satoh Takeo, Kumai Toshio, Murao Mei, Tsuchida Hiroki, Shima Yoshinori, Ogimoto Goichi, Fujino Tomoya, Kobayashi Shinichi, Kimura Kenjiro
Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
Hypertens Res. 2003 Apr;26(4):339-47. doi: 10.1291/hypres.26.339.
Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.
尽管已知高血压会加速糖尿病肾病的发展，但这一过程所涉及的机制尚不清楚。在本研究中，我们旨在以雄性Wistar肥胖大鼠（WFR）作为2型糖尿病模型，以雄性Wistar瘦大鼠（WLR）作为对照来阐明这些机制。每组大鼠从6周龄至14周龄喂食正常或高钠饮食。我们测定了血压和尿白蛋白排泄量（UAE）。在研究结束时，通过蛋白质印迹分析检测分离肾小球中丝裂原活化蛋白激酶（MAPK）和转化生长因子-β1（TGF-β1）的表达，并通过传统组织学确定肾小球病变的数量。高钠负荷导致WFR血压升高和UAE显著增加，但WLR未出现这种情况。高血压WFR的肾小球体积增大。四组之间c-Jun氨基末端激酶（JNK）的表达没有差异。相反，细胞外信号调节激酶1/2（ERK1/2）及其上游调节因子MAPK/ERK激酶1（MEK1）的表达在高血压WFR中增加。正常血压WFR中p38 MAPK的表达增加，在高血压WFR中进一步增强。此外，给WFR给予高钠负荷会增加TGF-β1的表达。总之，WFR中的全身性高血压通过MEK-ERK和p38 MAPK级联反应加速2型糖尿病中的糖尿病肾病。TGF-β1也参与了这一机制。
