Kamiyama Masumi, Garner Michelle K, Farragut Kristina M, Sofue Tadashi, Hara Taiga, Morikawa Takashi, Konishi Yoshio, Imanishi Masahito, Nishiyama Akira, Kobori Hiroyuki
1. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; ; 2. Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112, USA;
4. Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan;
Int J Biol Sci. 2014 May 3;10(5):530-42. doi: 10.7150/ijbs.8450. eCollection 2014.
In the intrarenal renin-angiotensin system, angiotensinogen levels are well known to be increased in diabetes, and these enhanced intrarenal angiotensinogen levels may initiate the development and accelerate the progression of diabetic nephropathy. However, the specific localization of the augmented angiotensinogen in proximal tubule segments in diabetes is still unknown. We investigated the detailed localization of angiotensinogen in 3 proximal tubule segments in the diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and the control Long-Evans Tokushima Otsuka (LETO) rats. We also prepared OLETF rats treated with angiotensin II type 1 receptor blocker, olmesartan or with a combination of vasodilator agents. Moreover, biopsied samples of human kidney cortex were used to confirm the results of animal studies. We examined the co-localization of angiotensinogen with segment-specific markers by double staining using fluorescence in situ hybridization and/or immunofluorescence. Angiotensinogen mRNA expression was barely detectable in segment 1. In segment 3, the area of angiotensinogen mRNA expression was augmented in the OLETF rats compared with the LETO rats. Angiotensinogen protein expression areas in segments 1 and 3 were also increased in the OLETF rats compared with the LETO rats. Chronic treatment with olmesartan ameliorated these areas of augmented angiotensinogen expression. Biopsied human kidney samples showed similar results. These data suggest that the augmented angiotensinogen mRNA levels in segment 3 and angiotensinogen protein levels in segments 1 and 3 may contribute to the progression of diabetic nephropathy.
在肾内肾素-血管紧张素系统中，众所周知糖尿病患者体内血管紧张素原水平会升高，而这些升高的肾内血管紧张素原水平可能引发糖尿病肾病的发生并加速其进展。然而，糖尿病时近端小管节段中血管紧张素原增加的具体定位仍不清楚。我们研究了血管紧张素原在糖尿病大冢长-艾氏-德岛肥胖（OLETF）大鼠和对照长-艾氏-德岛大冢（LETO）大鼠的3个近端小管节段中的详细定位。我们还制备了用1型血管紧张素II受体阻滞剂奥美沙坦或血管扩张剂组合治疗的OLETF大鼠。此外，使用人肾皮质活检样本以证实动物研究的结果。我们通过荧光原位杂交和/或免疫荧光双重染色检查了血管紧张素原与节段特异性标志物的共定位。在节段1中几乎检测不到血管紧张素原mRNA表达。在节段3中，与LETO大鼠相比，OLETF大鼠中血管紧张素原mRNA表达区域增加。与LETO大鼠相比，OLETF大鼠节段1和3中血管紧张素原蛋白表达区域也增加。用奥美沙坦长期治疗改善了这些血管紧张素原表达增加的区域。人肾活检样本显示了类似的结果。这些数据表明，节段3中血管紧张素原mRNA水平的增加以及节段1和3中血管紧张素原蛋白水平的增加可能有助于糖尿病肾病的进展。
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