Hayashi Koichi, Kanda Takeshi, Homma Koichiro, Tokuyama Hirobumi, Okubo Ken, Takamatsu Ichiro, Tatematsu Satoru, Kumagai Hiroo, Saruta Takao
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Metabolism. 2002 Dec;51(12):1553-61. doi: 10.1053/meta.2002.36311.
Although available evidence demonstrates that obesity manifests insulin resistance and causes glomerular sclerosis, it has not been determined whether insulin resistance alters the renal microvascular reactivity. This study examined whether insulin- and acetylcholine (ACH)-induced vasodilation was impaired in Zucker obese rats, and attempted to clarify the change in myogenic afferent arteriolar constriction, a determinant of glomerular pressure. Isolated perfused hydronephrotic rat kidneys were used to visualize the renal microcirculation. In Zucker lean rats, insulin (10 to 300 microU/mL) inhibited norepinephrine (NE)-induced afferent and efferent arteriolar constriction in a dose-dependent manner, with 112 % +/- 8% and 98% +/- 8% reversal at 300 microU/mL Similarly, ACH elicited dose-dependent dilation of these vessels. In Zucker obese rats, by contrast, afferent and efferent arterioles failed to dilate in response to insulin, and manifested diminished vasodilator responses to acetylcholine In the presence of nitro-L-arginine methylester (LNAME; 100 micromol/L), ACH (10 micromol/L) induced transient afferent arteriolar dilation (121% +/- 9% reversal) in Zucker lean rats, whereas this response was blunted in obese rats (72% +/- 8% reversal) Furthermore, myogenic afferent arteriolar constriction by elevating renal arterial pressure to 180 mm Hg was diminished in Zucker obese rats (-14% +/- 3% decrement in diameter), compared with that in lean rats (-23% +/- 2% decrement) Finally, the impairment in these vasodilator and vasoconstrictor responses was partially prevented by troglitazone, an insulin-sensitizing agent. Collectively, in insulin resistance, renal microvessels are refractory to the vasodilator action of insulin. Furthermore, "renal insulin resistance" is associated with the impaired vasodilator responses to ACH-induced nitric oxide (NO) and the diminished vasoconstrictor responses to pressure. The blunted myogenic afferent arteriolar constriction would allow glomerular hypertension, and in concert with the impaired endothelium-dependent vasodilation, could be responsible for the development of glomerular injury in obesity.
尽管现有证据表明肥胖会表现出胰岛素抵抗并导致肾小球硬化,但胰岛素抵抗是否会改变肾微血管反应性尚未确定。本研究检测了胰岛素和乙酰胆碱(ACH)诱导的血管舒张在 Zucker 肥胖大鼠中是否受损,并试图阐明肌源性传入小动脉收缩的变化,这是肾小球压力的一个决定因素。使用离体灌注的肾积水大鼠肾脏来观察肾微循环。在 Zucker 瘦大鼠中,胰岛素(10 至 300 μU/mL)以剂量依赖性方式抑制去甲肾上腺素(NE)诱导的传入和传出小动脉收缩,在 300 μU/mL 时分别有 112%±8%和 98%±8%的逆转。同样,ACH 引起这些血管的剂量依赖性舒张。相比之下,在 Zucker 肥胖大鼠中,传入和传出小动脉对胰岛素无舒张反应,且对乙酰胆碱的血管舒张反应减弱。在存在硝基-L-精氨酸甲酯(LNAME;100 μmol/L)的情况下,ACH(10 μmol/L)在 Zucker 瘦大鼠中诱导短暂的传入小动脉舒张(121%±9%逆转),而在肥胖大鼠中这种反应减弱(72%±8%逆转)。此外,与瘦大鼠相比,将肾动脉压力升高至 180 mmHg 时,Zucker 肥胖大鼠的肌源性传入小动脉收缩减弱(直径减少-14%±3%),而瘦大鼠为-23%±2%。最后,胰岛素增敏剂曲格列酮部分预防了这些血管舒张和血管收缩反应的受损。总体而言,在胰岛素抵抗中,肾微血管对胰岛素的血管舒张作用具有抗性。此外,“肾胰岛素抵抗”与对 ACH 诱导的一氧化氮(NO)的血管舒张反应受损以及对压力的血管收缩反应减弱有关。肌源性传入小动脉收缩减弱会导致肾小球高压,并且与内皮依赖性血管舒张受损协同作用,可能是肥胖中肾小球损伤发展的原因。