Jacobi J, Porst M, Cordasic N, Namer B, Schmieder R E, Eckardt K-U, Hilgers K F
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Kidney Int. 2006 Jun;69(11):2013-21. doi: 10.1038/sj.ki.5000448.
Kidney disease is associated with increased cardiovascular morbidity, but underlying mechanisms are poorly understood. We tested the hypothesis that chronic renal insufficiency impairs angioadaptation in a rat model of hindlimb ischemia. Twenty male Sprague-Dawley rats (8 weeks old) underwent subtotal nephrectomy (5/6SNX) or sham surgery (each n=10). Ten weeks later, unilateral hindlimb ischemia was induced in all animals. Hindlimb perfusion was assessed by laser Doppler perfusion imaging and fluorescent microsphere injection studies 2 weeks after surgery. Ischemia-induced angiogenesis was measured by analyzing capillary density using CD31 immunofluorescence. Expression of vascular endothelial growth factor (VEGF), its receptors (VEGFRs) and inducible as well as endothelial nitric oxide (NO) synthase was measured by real-time reverse transcription-polymerase chain reaction. Laser Doppler hindpaw perfusion was significantly reduced in 5/6SNX compared to sham-operated animals. Impaired hindlimb re-perfusion in 5/6SNX vs control rats was confirmed by fluorescent microsphere injection studies (relative perfusion of ischemic vs non-ischemic limb: 68.9+/-6.4 vs 92.4+/-3.6%, P=0.005). Ischemic skeletal muscle neovascularization increased to a greater extent in sham-operated compared to 5/6SNX rats (69+/-8 vs 29+/-7%, P<0.05). VEGF and VEGFR-1/2 mRNA expression increased in ischemic hindlimbs of control rats, whereas no change or a decrease was observed in 5/6SNX. In contrast, inducible and endothelial NO synthase expression did not significantly differ between sham and 5/6SNX rats. Chronic renal insufficiency impairs angiogenesis and limb perfusion in a rat hindlimb ischemia model. Impaired angioadaptation may contribute to the poor prognosis of patients with renal failure suffering from peripheral arterial disease.
肾脏疾病与心血管疾病发病率增加相关，但潜在机制尚不清楚。我们在大鼠后肢缺血模型中检验了慢性肾功能不全损害血管适应性这一假说。20只雄性Sprague-Dawley大鼠（8周龄）接受了次全肾切除术（5/6SNX）或假手术（每组n = 10）。10周后，对所有动物进行单侧后肢缺血诱导。术后2周通过激光多普勒灌注成像和荧光微球注射研究评估后肢灌注。通过使用CD31免疫荧光分析毛细血管密度来测量缺血诱导的血管生成。通过实时逆转录聚合酶链反应测量血管内皮生长因子（VEGF）、其受体（VEGFRs）以及诱导型和内皮型一氧化氮（NO）合酶的表达。与假手术动物相比，5/6SNX组的激光多普勒后爪灌注显著降低。荧光微球注射研究证实5/6SNX组与对照大鼠相比后肢再灌注受损（缺血肢体与非缺血肢体的相对灌注：68.9±6.4% 对92.4±3.6%，P = 0.005）。与5/6SNX大鼠相比，假手术大鼠缺血骨骼肌的新血管形成增加幅度更大（69±8% 对29±7%，P<0.05）。对照大鼠缺血后肢中VEGF和VEGFR-1/2 mRNA表达增加，而在5/6SNX组中未观察到变化或有所降低。相反，假手术组和5/6SNX组大鼠之间诱导型和内皮型NO合酶表达无显著差异。慢性肾功能不全损害大鼠后肢缺血模型中的血管生成和肢体灌注。血管适应性受损可能导致患有外周动脉疾病的肾衰竭患者预后不良。
