The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats
The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats
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DOI：
10.1111/j.1523-1755.2004.00407.x
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发表时间：
2004-02-01
影响因子：
19.6
通讯作者：
Makino, H
中科院分区：
文献类型：
--
作者：
Hiragushi, K;Wada, J;Makino, H
背景肾上腺髓质素（adrenomedullin，AM）通过与血管内皮细胞上特异性的受体结合，刺激一氧化氮的产生，增强血管舒张功能，可能参与糖尿病肾病早期肾小球毛细血管扩张。在注射后4周，使用链脲佐菌素（STZ）诱导的糖尿病Sprague-Dawley大鼠进行AM、RAPM 2和RAMP 3的表达研究。进行肾组织、血浆和尿液中AM肽水平的测量。以人主动脉内皮细胞（HAEC）为材料，研究葡萄糖诱导AM产生与一氧化氮释放之间的功能联系。STZ大鼠表现为肾小球肥大和尿NO2-和NO3-排泄增加。通过北方印迹分析，AM和RAPM 2 mRNA在STZ大鼠肾脏中显著增加，而RAMP 3 mRNA没有改变。在STZ大鼠中，AM肽主动分泌到尿液中（1280 +/- 360 fmol/天与对照组110 +/- 36 fmol/天）。对照组大鼠肾皮质和髓质集合管细胞中AM肽表达较强，STZ组大鼠肾传入小动脉和肾小球中AM肽及其mRNA表达较强。RAMP 2在对照组大鼠的传入小动脉中表达，而在肾小球中不表达，在STZ大鼠的肾小球内皮细胞中表达上调。在HAEC培养中，D-葡萄糖刺激AM和NO的产生，AM反义寡核苷酸可抑制AM和NO的产生。1型糖尿病急性期肾小球毛细血管选择性扩张可能与AM和RAMP 2在输入小动脉和肾小球的表达上调有关。
Background. Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy.Methods. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release.Results. STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, D-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides.Conclusion. Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.