Gannon Kimberly P, McKey Susan E, Stec David E, Drummond Heather A
Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi.
Department of Physiology and Biophysics and the Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi
Am J Physiol Renal Physiol. 2015 Feb 15;308(4):F339-48. doi: 10.1152/ajprenal.00572.2014. Epub 2014 Dec 17.
Previous studies from our laboratory have suggested that degenerin proteins contribute to myogenic constriction, a mechanism of blood flow regulation and protection against pressure-dependent organ injury, in renal vessels. The goal of the present study was to determine the importance of one family member, acid-sensing ion channel 2 (ASIC2), in myogenic constriction of renal interlobar arteries, myogenic regulation of whole kidney blood flow, renal injury, and blood pressure using ASIC2(+/+), ASIC2(+/-), and ASIC2(-/-) mice. Myogenic constriction in renal interlobar arteries was impaired in ASIC2(+/-) and ASIC2(-/-) mice, whereas constriction to KCl/phenylephrine was unchanged. Correction of whole kidney renal vascular resistance (RVR) during the first 5 s after a 10- to 20-mmHg step increase in perfusion pressure, a timeframe associated with myogenic-mediated correction of RVR, was slowed (4.2 ± 0.9, 0.3 ± 0.7, and 2.4 ± 0.3 resistance units/s in ASIC2(+/+), ASIC2(+/-), and ASIC2(-/-) mice). Although modest reductions in function were observed in ASIC2(-/-) mice, greater reductions were observed in ASIC2(+/-) mice, which may be explained by protein-protein interactions of ASIC2 with other degenerins. Isolated glomeruli from ASIC2(+/-) and ASIC2(-/-) mice had modest alterations in the expression of inflammation and injury markers (transforming growth factor-β, mouse anti-target of antiproliferative antibody-1, and nephrin), whereas ASIC2(+/-) mice had an increase in the remodeling marker collagen type III. Consistent with a more severe loss of function, mean arterial pressure was increased in ASIC2(+/-) mice (131 ± 3 mmHg) but not in ASIC2(-/-) mice (122 ± 3 vs. 117 ± 2 mmHg in ASIC2(+/+) mice). These results suggest that ASIC2 contributes to transduction of the renal myogenic response and are consistent with the protective role of myogenic constriction against renal injury and hypertension.
我们实验室之前的研究表明，退化蛋白有助于肾血管中的肌源性收缩，这是一种血流调节机制，可保护器官免受压力依赖性损伤。本研究的目的是使用 ASIC2(+/+)、ASIC2(+/-) 和 ASIC2(-/-) 小鼠，确定退化蛋白家族成员之一酸敏感离子通道 2（ASIC2）在肾叶间动脉肌源性收缩、全肾血流的肌源性调节、肾损伤和血压方面的重要性。ASIC2(+/-) 和 ASIC2(-/-) 小鼠肾叶间动脉的肌源性收缩受损，而对氯化钾/去氧肾上腺素的收缩反应未改变。在灌注压力从 10 至 20 mmHg 逐步升高后的前 5 秒内，全肾肾血管阻力（RVR）的校正减缓（ASIC2(+/+)、ASIC2(+/-) 和 ASIC2(-/-) 小鼠分别为 4.2±0.9、0.3±0.7 和 2.4±0.3 阻力单位/秒），这一时间段与肌源性介导的 RVR 校正相关。虽然在 ASIC2(-/-) 小鼠中观察到功能有适度降低，但在 ASIC2(+/-) 小鼠中降低更为明显，这可能是由于 ASIC2 与其他退化蛋白的蛋白质-蛋白质相互作用所致。来自 ASIC2(+/-) 和 ASIC2(-/-) 小鼠的分离肾小球在炎症和损伤标志物（转化生长因子-β、抗增殖抗体-1 的小鼠抗靶点和 Nephrin）的表达上有适度改变，而 ASIC2(+/-) 小鼠的重塑标志物 III 型胶原增加。与更严重的功能丧失一致，ASIC2(+/-) 小鼠的平均动脉压升高（131±3 mmHg），而 ASIC2(-/-) 小鼠未升高（ASIC2(+/+) 小鼠为 117±2 mmHg，ASIC2(-/-) 小鼠为 122±3 mmHg）。这些结果表明，ASIC2 有助于肾肌源性反应的转导，并且与肌源性收缩对肾损伤和高血压的保护作用一致。
