Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, University Medical Center Groningen, A. Deusinglaan 1, Groningen, The Netherlands.
Am J Physiol Renal Physiol. 2012 Oct 15;303(8):F1187-95. doi: 10.1152/ajprenal.00653.2011. Epub 2012 Jul 11.
Previously, it was shown that individuals with good baseline (a priori) endothelial function in isolated (in vitro) renal arteries developed less renal damage after 5/6 nephrectomy (5/6Nx; Gschwend S, Buikema H, Navis G, Henning RH, de Zeeuw D, van Dokkum RP. J Am Soc Nephrol 13: 2909-2915, 2002). In this study, we investigated whether preexisting glomerular vascular integrity predicts subsequent renal damage after 5/6Nx, using in vivo intravital microscopy and in vitro myogenic constriction of small renal arteries. Moreover, we aimed to elucidate the role of renal ANG II type 1 receptor (AT1R) expression in this model. Anesthetized rats underwent intravital microscopy to visualize constriction to ANG II of glomerular afferent and efferent arterioles, with continuous measurement of blood pressure, heart rate, and renal blood flow. Thereafter, 5/6Nx was performed, interlobar arteries were isolated from the extirpated kidney, and myogenic constriction was assessed in a perfused vessel setup. Blood pressure and proteinuria were assessed weekly for 12 wk, and focal glomerulosclerosis (FGS) was determined at the end of study. Relative expression AT1R in the kidney cortex obtained at 5/6Nx was determined by PCR. Infusion of ANG II induced significant constriction of both afferent and efferent glomerular arterioles, which strongly positively correlated with proteinuria and FGS at 12 wk after 5/6Nx. Furthermore, in vitro measured myogenic constriction of small renal arteries negatively correlated with proteinuria 12 wk after 5/6Nx. Moreover, in vivo vascular reactivity negatively correlated with in vitro reactivity. Additionally, relative expression of AT1R positively correlated with responses of glomerular arterioles and with markers of renal damage. Both in vivo afferent and efferent responses to ANG II and in vitro myogenic constriction of small renal arteries in the healthy rat predict the severity of renal damage induced by 5/6Nx. This vascular responsiveness is highly dependent on AT1R expression. Intraorgan vascular integrity may provide a useful tool to guide the prevention and treatment of renal end-organ damage.
先前的研究表明，在孤立（体外）肾动脉中具有良好基线（先验）内皮功能的个体，在 5/6 肾切除术后（5/6Nx；Gschwend S、Buikema H、Navis G、Henning RH、de Zeeuw D、van Dokkum RP. J Am Soc Nephrol 13: 2909-2915, 2002）发展出较少的肾损伤。在这项研究中，我们使用活体显微镜检查和体外肌源性收缩小型肾动脉来研究预先存在的肾小球血管完整性是否可以预测 5/6Nx 后的肾脏损伤。此外，我们旨在阐明该模型中肾血管紧张素 II 1 型受体（AT1R）表达的作用。麻醉大鼠接受活体显微镜检查，以观察肾小球传入和传出小动脉对 ANG II 的收缩，同时连续测量血压、心率和肾血流量。此后，进行 5/6Nx，从切除的肾脏中分离出叶间动脉，并在灌注血管装置中评估肌源性收缩。每周评估血压和蛋白尿 12 周，并在研究结束时确定局灶性肾小球硬化（FGS）。通过 PCR 确定 5/6Nx 时获得的肾脏皮质中 AT1R 的相对表达。ANG II 的输注诱导了传入和传出肾小球小动脉的显著收缩，这与 5/6Nx 后 12 周的蛋白尿和 FGS 强烈正相关。此外，5/6Nx 后 12 周，体外测量的小型肾动脉肌源性收缩与蛋白尿呈负相关。此外，活体血管反应性与体外反应性呈负相关。此外，AT1R 的相对表达与肾小球小动脉的反应性和肾脏损伤标志物呈正相关。健康大鼠体内的传入和传出对 ANG II 的反应以及体外小型肾动脉的肌源性收缩均可以预测 5/6Nx 引起的肾脏损伤的严重程度。这种血管反应性高度依赖于 AT1R 的表达。器官内血管完整性可能是指导预防和治疗肾脏终末器官损伤的有用工具。
