Adenine-induced chronic renal failure causes decreased aortic relaxation rate and altered expression of genes involved in excitation-contraction coupling in vascular smooth muscle cells

Rats with adenine-induced chronic renal failure (A-CRF) develop a reduction in the rate of relaxation of the thoracic aorta. The primary aim of this study was to elucidate the mechanisms underlying this abnormality. Male Sprague-Dawley rats received either chow containing adenine or were pair-fed with normal chow (controls). After 8-14 weeks arterial functions were analyzed ex vivo using wire myography and the thoracic aorta was analyzed by DNA microarray. Plasma creatinine levels were elevated ~8-fold in A-CRF rats. The rate of vascular relaxation following wash-out of KCl was reduced in A-CRF rats vs. controls in the thoracic aorta (P<0.01), abdominal aorta (P<0.05), and common carotid artery (P<0.05), but not in the common femoral artery. Endothelial denudation exaggerated the impairment in relaxation of thoracic aortas. Relaxation rates of thoracic aortas increased (P<0.01), but were not normalized, in response to wash-out of KCl with Ca2+-free buffer. Microarray and qRT-PCR analyses revealed altered gene expression levels for a number of genes involved in vascular smooth muscle cell excitation-contraction coupling in aortas of A-CRF rats. In conclusion, rats with A-CRF show a marked reduction in the rate of relaxation of larger conduit arteries localized proximal to the common femoral artery. This abnormality may be caused by reduced cytosolic Ca2+ clearance in vascular smooth muscle cells secondary to dysregulation of genes involved in excitation-contraction coupling. Microarray expression analysis of thoracic aortas from rats with adenine-induced chronic renal failure

腺嘌呤诱导慢性肾衰竭（adenine-induced chronic renal failure, A-CRF）模型大鼠的胸主动脉舒张速率呈现降低。本研究的核心目的为阐明该血管功能异常的潜在分子机制。雄性斯普拉-道来（Sprague-Dawley, SD）大鼠被随机分为两组：一组喂食含腺嘌呤的饲料，另一组采用配对喂养法喂食正常饲料以作为对照组。造模8~14周后，采用离体钢丝肌描记法（wire myography）分析动脉血管功能，并通过DNA微阵列（DNA microarray）技术检测胸主动脉的基因表达谱。A-CRF模型大鼠的血浆肌酐水平较对照组升高约8倍。相较于对照组，A-CRF模型大鼠的胸主动脉（P<0.01）、腹主动脉（P<0.05）以及颈总动脉（P<0.05）在KCl洗脱后的血管舒张速率均显著降低，但股总动脉未观察到该异常。内皮剥脱会加重胸主动脉舒张功能的损伤程度。采用无钙缓冲液（Ca²⁺-free buffer）洗脱KCl后，胸主动脉的舒张速率虽有所升高（P<0.01），但并未恢复至正常水平。微阵列与实时荧光定量聚合酶链反应（qRT-PCR）分析结果显示，A-CRF模型大鼠主动脉中多个参与血管平滑肌细胞兴奋-收缩耦联的基因表达水平发生显著改变。综上，A-CRF模型大鼠的近端至股总动脉区域的大型传导动脉舒张速率均出现明显降低。该血管功能异常可能是由于血管平滑肌细胞的胞质钙离子清除能力下降所致，而这一变化继发于兴奋-收缩耦联相关基因的表达失调。针对腺嘌呤诱导慢性肾衰竭模型大鼠胸主动脉的微阵列基因表达分析