Department of Anatomy and BK 21 Project, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Am J Physiol Renal Physiol. 2010 May;298(5):F1118-29. doi: 10.1152/ajprenal.00701.2009. Epub 2010 Feb 17.
Reactive oxygen species (ROS) function as an inducer of cell death and survival or proliferative factor, in a cell-type-specific and concentration-dependent manner. All of these roles are critical to ischemia-induced renal functional impairment and progressive fibrotic changes in the kidney. In an effort to define the role of ROS in the proliferation of tubular epithelial cells and of interstitial cells in kidneys recovering after ischemia and reperfusion (I/R) injury, experimental mice were subjected to 30 min of bilateral kidney ischemia and administered with manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, from 2 to 15 days after I/R for 14 days daily (earlier and longer) and from 8 to 15 days after I/R for 8 days daily (later and shorter). Cell proliferation was assessed via 5'-bromo-2'-deoxyuridine (BrdU) incorporation assays for 20 h before the harvest of kidneys. After I/R, the numbers of BrdU-incorporating cells increased both in the tubules and interstitium. MnTMPyP administration was shown to accelerate the proliferation of tubular epithelial cells, presenting tubule-specific marker proteins along tubular segments, whereas it attenuated the proliferation of interstitial cells, evidencing α-smooth muscle actin, fibroblast-specific protein-1, F4/80, and NADPH oxidase-2 proteins; these results indicated that ROS attenuates tubular cell regeneration, but accelerates interstitial cell proliferation. Earlier and longer MnTMPyP treatment more effectively inhibited tissue superoxide formation, the increment of interstitial cells, and the decrement of epithelial cells compared with later and shorter treatment. After I/R, apoptotic cells appeared principally in the tubular epithelial cells, but not in the interstitial cells, thereby indicating that ROS is harmful in tubule cells, but is not in interstitial cells. In conclusion, ROS generated after I/R injury in cell proliferation and death performs a cell-type-specific and concentration-dependent role, even within the same tissues, and timely intervention of ROS is crucial for effective therapies.
活性氧（ROS）作为细胞死亡和存活或增殖因子的诱导剂，以细胞类型特异性和浓度依赖性方式发挥作用。所有这些作用对于缺血引起的肾功能损害和肾脏进行性纤维化变化都至关重要。为了确定 ROS 在缺血再灌注（I/R）损伤后肾小管上皮细胞和间质细胞增殖中的作用，实验小鼠在 I/R 后 2 至 15 天内每天接受双侧肾脏缺血 30 分钟，并给予锰（III）四（1-甲基-4-吡啶基）卟啉（MnTMPyP），一种超氧化物歧化酶模拟物，持续 14 天（更早和更长时间），或在 I/R 后 8 至 15 天内每天接受 8 天（更晚和更短时间）。在收获肾脏前 20 小时通过 5'-溴-2'-脱氧尿苷（BrdU）掺入测定评估细胞增殖。在 I/R 后，BrdU 掺入细胞的数量在肾小管和间质中均增加。MnTMPyP 给药被证明可加速管状上皮细胞的增殖，呈现沿管状段的管状特异性标记蛋白，而同时它可减弱间质细胞的增殖，表现出α-平滑肌肌动蛋白，成纤维细胞特异性蛋白-1，F4/80 和 NADPH 氧化酶-2 蛋白；这些结果表明 ROS 可减弱管状细胞再生，但可加速间质细胞增殖。与更晚和更短的治疗相比，更早和更长时间的 MnTMPyP 治疗更有效地抑制了组织中超氧化物的形成，间质细胞的增加和上皮细胞的减少。在 I/R 后，凋亡细胞主要出现在肾小管上皮细胞中，但不出现在间质细胞中，这表明 ROS 对肾小管细胞有害，但对间质细胞无害。总之，I/R 损伤后在细胞增殖和死亡中产生的 ROS 发挥了细胞类型特异性和浓度依赖性作用，即使在同一组织中也是如此，及时干预 ROS 对于有效的治疗至关重要。
