Verma Rajeev, Chopra Avijeet, Giardina Charles, Sabbisetti Venkata, Smyth Joan A, Hightower Lawrence E, Perdrizet George A
Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA,
Cell Stress Chaperones. 2015 May;20(3):495-505. doi: 10.1007/s12192-015-0574-3. Epub 2015 Feb 4.
The disease burden from diabetic kidney disease is large and growing. Effective therapies are lacking, despite an urgent need. Hyperbaric oxygen therapy (HBOT) activates Nrf2 and cellular antioxidant defenses; therefore, it may be generally useful for treating conditions that feature chronic oxidative tissue damage. Herein, we determined how periodic exposure to oxygen at elevated pressure affected type 2 diabetes mellitus-related changes in the kidneys of db/db mice. Two groups of db/db mice, designated 2.4 ATA and 1.5 ATA, were treated four times per week with 100 % oxygen at either 1.5 or 2.4 ATA (atmospheres absolute) followed by tests to assess kidney damage and function. The sham group of db/db mice and the Hets group of db/+ mice were handled but did not receive HBOT. Several markers of kidney damage were reduced significantly in the HBOT groups including urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (CyC) along with significantly lower levels of caspase-3 activity in kidney tissue extracts. Other stress biomarkers also showed trends to improvement in the HBOT groups, including urinary albumin levels. Expressions of the stress response genes NRF2, HMOX1, MT1, and HSPA1A were reduced in the HBOT groups at the end of the experiment, consistent with reduced kidney damage in treated mice. Urinary albumin/creatinine ratio (ACR), a measure of albuminuria, was significantly reduced in the db/db mice receiving HBOT. All of the db/db mouse groups had qualitatively similar changes in renal histopathology. Glycogenated nuclei, not previously reported in db/db mice, were observed in these three experimental groups but not in the control group of nondiabetic mice. Overall, our findings are consistent with therapeutic HBOT alleviating stress and damage in the diabetic kidney through cytoprotective responses. These findings support an emerging paradigm in which tissue oxygenation and cellular defenses effectively limit damage from chronic oxidative stress more effectively than chemical antioxidants.
糖尿病肾病的疾病负担巨大且不断增加。尽管迫切需要有效的治疗方法，但目前仍很缺乏。高压氧疗法（HBOT）可激活Nrf2和细胞抗氧化防御；因此，它可能对治疗以慢性氧化组织损伤为特征的疾病普遍有用。在此，我们确定了在高压下定期吸氧如何影响db/db小鼠肾脏中与2型糖尿病相关的变化。将两组db/db小鼠分别命名为2.4 ATA组和1.5 ATA组，每周用1.5或2.4个绝对大气压（ATA）的纯氧治疗4次，随后进行测试以评估肾脏损伤和功能。对db/db小鼠的假手术组和db/+小鼠的杂合子组进行了处理，但未接受高压氧治疗。高压氧治疗组中，几种肾脏损伤标志物显著降低，包括尿液生物标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和胱抑素C（CyC），同时肾脏组织提取物中的半胱天冬酶-3活性水平也显著降低。其他应激生物标志物在高压氧治疗组中也呈现改善趋势，包括尿白蛋白水平。在实验结束时，高压氧治疗组中应激反应基因NRF2、HMOX1、MT1和HSPA1A的表达降低，这与治疗小鼠肾脏损伤减轻一致。接受高压氧治疗的db/db小鼠的尿白蛋白/肌酐比值（ACR）显著降低。所有db/db小鼠组的肾脏组织病理学变化在性质上相似。在这三个实验组中观察到了糖原核，这在db/db小鼠中此前未被报道，而在非糖尿病小鼠的对照组中未观察到。总体而言，我们的研究结果表明，治疗性高压氧疗法通过细胞保护反应减轻了糖尿病肾脏的应激和损伤。这些发现支持了一种新出现的模式，即组织氧合和细胞防御比化学抗氧化剂更有效地限制慢性氧化应激造成的损伤。
