Centre for Kidney Disease Research, University of Queensland School of Medicine, Princess Alexandra Hospital, Brisbane, Australia.
Cytotherapy. 2012 Feb;14(2):162-72. doi: 10.3109/14653249.2011.613927. Epub 2011 Sep 28.
Ischemia-reperfusion (IR) injury is a common cause of acute renal failure. Bone marrow (BM)-derived mesenchymal stromal cells (MSC) delivered after renal IR are renoprotective, but knowledge of the protective mechanism is still in development. This investigation analyzed the protective molecular mechanisms of MSC, in particular relating to modulated oxidative stress.
In vivo and in vitro models of renal IR were analyzed with and without MSC. In vivo, adult male Sprague-Dawley rats were subjected to 40-min unilateral renal IR. Rat BM-derived MSC were administered at 24 h post-IR (IR + MSC). Other groups had IR but no MSC, or MSC but no ischemia (all groups n = 4). Apoptosis, inflammation, oxidative stress and reparative signal transduction molecules or growth factors were studied 4 days post-IR. In vitro, protection by MSC against oxidative stress (0.4 mm hydrogen peroxide) was investigated using rat renal tubular epithelial cells (NRK52E) with or without MSC in co-culture (tissue culture trans-well inserts), followed by similar analyses to the in vivo investigation.
In vivo, kidneys of IR + MSC animals had significantly increased cell proliferation/regeneration (cells positive for proliferating cell nuclear antigen, expression of epidermal growth factor), increased heme-oxygenase-1 (improved cell survival, anti-oxidant) and decreased 8-OHdG (decreased oxidative stress). In vitro, MSC delivered with oxidative stress significantly decreased apoptosis and Bax (pro-apoptotic protein), and increased mitosis and phospho-ERK1/2, thereby minimizing the damaging outcome and maximizing the regenerative effect after oxidative stress.
The benefits of MSC, in IR, were primarily pro-regenerative, sometimes anti-apoptotic, and novel anti-oxidant mechanisms were identified.
缺血再灌注（IR）损伤是急性肾衰竭的常见原因。骨髓（BM）来源的间充质基质细胞（MSC）在肾 IR 后输送具有肾保护作用，但对其保护机制的认识仍在不断发展。本研究分析了 MSC 的保护分子机制，特别是与调节氧化应激有关的机制。
在有和没有 MSC 的情况下分析肾 IR 的体内和体外模型。在体内，成年雄性 Sprague-Dawley 大鼠接受 40 分钟单侧肾 IR。IR 后 24 小时给予大鼠 BM 来源的 MSC（IR+MSC）。其他组有 IR 但没有 MSC，或有 MSC 但没有缺血（所有组 n=4）。IR 后 4 天研究了细胞凋亡、炎症、氧化应激和修复信号转导分子或生长因子。在体外，使用大鼠肾小管上皮细胞（NRK52E）在共培养（组织培养 Trans-well 插入物）中用或不用 MSC 来研究 MSC 对氧化应激（0.4mm 过氧化氢）的保护作用，然后对体内研究进行类似分析。
在体内，IR+MSC 动物的肾脏细胞增殖/再生（增殖细胞核抗原阳性细胞，表皮生长因子表达）明显增加，血红素加氧酶-1（改善细胞存活，抗氧化）增加，8-OHdG（减少氧化应激）减少。在体外，在氧化应激下输送的 MSC 显著减少细胞凋亡和 Bax（促凋亡蛋白），增加有丝分裂和磷酸化 ERK1/2，从而最大限度地减少氧化应激后的损伤后果并最大限度地发挥再生作用。
MSC 在 IR 中的益处主要是促再生的，有时是抗凋亡的，并且确定了新的抗氧化机制。
