Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Veterans Affairs Medical Center, Birmingham, Alabama.
Am J Physiol Renal Physiol. 2021 Mar 1;320(3):F429-F441. doi: 10.1152/ajprenal.00500.2020. Epub 2021 Jan 25.
Renal autoregulation is critical in maintaining stable renal blood flow (RBF) and glomerular filtration rate (GFR). Renal ischemia-reperfusion (IR)-induced kidney injury is characterized by reduced RBF and GFR. The mechanisms contributing to renal microvascular dysfunction in IR have not been fully determined. We hypothesized that increased reactive oxygen species (ROS) contributed to impaired renal autoregulatory capability in IR rats. Afferent arteriolar autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. IR was induced by 60 min of bilateral renal artery occlusion followed by 24 h of reperfusion. Afferent arterioles from sham rats exhibited normal autoregulatory behavior. Stepwise increases in perfusion pressure caused pressure-dependent vasoconstriction to 65 ± 3% of baseline diameter (13.2 ± 0.4 μm) at 170 mmHg. In contrast, pressure-mediated vasoconstriction was markedly attenuated in IR rats. Baseline diameter averaged 11.7 ± 0.5 µm and remained between 90% and 101% of baseline over 65-170 mmHg, indicating impaired autoregulatory function. Acute antioxidant administration (tempol or apocynin) to IR kidneys for 20 min increased baseline diameter and improved autoregulatory capability, such that the pressure-diameter profiles were indistinguishable from those of sham kidneys. Furthermore, the addition of polyethylene glycol superoxide dismutase or polyethylene glycol-catalase to the perfusate blood also restored afferent arteriolar autoregulatory responsiveness in IR rats, indicating the involvement of superoxide and/or hydrogen peroxide. IR elevated mRNA expression of NADPH oxidase subunits and monocyte chemoattractant protein-1 in renal tissue homogenates, and this was prevented by tempol pretreatment. These results suggest that ROS accumulation, likely involving superoxide and/or hydrogen peroxide, impairs renal autoregulation in IR rats in a reversible fashion. Renal ischemia-reperfusion (IR) leads to renal microvascular dysfunction manifested by impaired afferent arteriolar autoregulatory efficiency. Acute administration of scavengers of reactive oxygen species, polyethylene glycol-superoxide dismutase, or polyethylene glycol-catalase following renal IR restored afferent arteriolar autoregulatory capability in IR rats, indicating that renal IR led to reversible impairment of afferent arteriolar autoregulatory capability. Intervention with antioxidant treatment following IR may improve outcomes in patients by preserving renovascular autoregulatory function and potentially preventing the progression to chronic kidney disease after acute kidney injury.
肾自动调节对于维持稳定的肾血流（RBF）和肾小球滤过率（GFR）至关重要。肾缺血再灌注（IR）引起的肾损伤的特征是 RBF 和 GFR 降低。导致 IR 中肾微血管功能障碍的机制尚未完全确定。我们假设活性氧（ROS）的增加导致 IR 大鼠肾自动调节能力受损。使用灌流肾髓质肾单位制备来评估入球小动脉自动调节行为。通过双侧肾动脉闭塞 60 分钟诱导 IR，然后再灌注 24 小时。假手术大鼠的入球小动脉表现出正常的自动调节行为。逐步增加灌注压会导致压力依赖性血管收缩，使血管直径在 170mmHg 时收缩至基线直径的 65±3%（13.2±0.4μm）。相比之下，IR 大鼠的压力介导的血管收缩明显减弱。基线直径平均为 11.7±0.5μm，在 65-170mmHg 之间保持在基线的 90%到 101%之间，表明自动调节功能受损。将急性抗氧化剂（tempol 或 apocynin）给予 IR 肾脏 20 分钟可增加基线直径并改善自动调节能力，使得压力-直径曲线与假手术肾脏的曲线无法区分。此外，向灌流血液中添加聚乙二醇超氧化物歧化酶或聚乙二醇过氧化氢酶也恢复了 IR 大鼠入球小动脉自动调节反应性，表明超氧化物和/或过氧化氢的参与。IR 导致肾组织匀浆中 NADPH 氧化酶亚基和单核细胞趋化蛋白-1 的 mRNA 表达升高，而 tempol 预处理可预防这种升高。这些结果表明，ROS 积聚，可能涉及超氧化物和/或过氧化氢，以可逆转的方式损害 IR 大鼠的肾自动调节。肾缺血再灌注（IR）导致肾微血管功能障碍，表现为入球小动脉自动调节效率受损。在肾 IR 后立即给予活性氧清除剂、聚乙二醇超氧化物歧化酶或聚乙二醇过氧化氢酶可恢复 IR 大鼠入球小动脉自动调节能力，表明肾 IR 导致入球小动脉自动调节能力可逆性受损。IR 后进行抗氧化治疗干预可能通过维持肾血管自动调节功能并可能防止急性肾损伤后慢性肾脏病的进展来改善患者的预后。
