在肾缺血再灌注损伤期间对患有糖尿病的食蟹猴(猕猴)肾脏中选定标记物的评估。

Tae M Kim, Kyo W Lee, Hong D Kim, Sung O Hong, Hye J Cho, Je H Yang, Sung J Kim, Jae B Park
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摘要

我们先前报道,诱导的1型糖尿病(DM)增加了食蟹猴缺血再灌注损伤(IRI)诱导的急性肾损伤的易感性。在这项后续研究中,我们比较了患有和不患有糖尿病的双侧肾IRI猴子肾组织中选定标志物的表达。所有组织均取自原始研究。在缺血前和缺血后24和48小时进行肾活检,检查KI-67(肾小管增殖)、Na+/K+ATP酶(钠钾泵)、TNF-α(肿瘤坏死因子-α,炎症)、CD31(微血管)、CD3(T细胞)、2种纤维化标志物(成纤维细胞特异性蛋白-1、FSP-1、α-平滑肌凝集素、α-SMA)和裂解胱天蛋白酶3(细胞凋亡)的表达。通常,这些标志物在患有和不患有糖尿病的猴子中的表达不同。与非糖尿病猴子相比,糖尿病猴子在急性肾损伤(AKI)的进展过程中有更多的细胞表达KI-67。Na+/K+ATP酶在基线时仅在非糖尿病猴的基底外侧肾小管区域明显表达。在48小时时,其在DM猴的基底外侧区域的表达不可见,但在非DM猴的细胞间连接中仍然存在。TNF-α的表达在DM缺血前和缺血后48h明显增高。在缺血前和缺血后24小时,两组CD31阳性毛细血管的数量没有差异,尽管在24小时时DM中发现更多的血管塌陷。在48小时时,DM中的毛细血管数量比非DM动物少。在缺血后24和48小时,DM猴的间质CD3阳性细胞比非DM猴多。最后,在24和48小时,糖尿病患者中FSP-1表达的细胞比非糖尿病患者更丰富。我们的结果表明,DM通过影响肾小管增殖、毛细血管密度、T细胞浸润以及改变参与离子通道、炎症和纤维变性的各种基因的蛋白和mRNA表达,来加重肾缺血/再灌注损伤的恢复。这项观察性研究的结果表明,糖尿病通过影响多个事件,包括食蟹猴的肾小管坏死、增殖、功能、炎症和诱导毛细血管稀疏,从而加重肾缺血/再灌注的恢复。
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Evaluation of Selected Markers in Kidneys of Cynomolgus Monkey (Macaca fascicularis) with Induced Diabetes during Renal Ischemia-reperfusion Injury.

We previously reported that induced type 1 diabetes mellitus (DM) increases the susceptibility of acute kidney injury inducedby ischemia-reperfusion injury (IRI) in cynomolgus monkeys. In this follow-up study, we compared the expression ofselected markers in the renal tissues of monkeys subjected to bilateral renal IRI with and without diabetes. All tissues wereobtained from the original study. Renal biopsies were obtained before and 24 and 48 h after ischemia and were examinedfor expression of KI-67 (tubular proliferation), Na+/K+ ATPase (sodium-potassium pump), TNF-α (tumor necrosis factor-α,inflammation), CD31 (microvessels), CD3 (T-cells), 2 fibrotic markers (fibroblast specific protein-1, FSP-1; α-smooth muscleactin, α-SMA), and cleaved caspase 3 (apoptosis). Generally, the expression of these markers differed in monkeys with andwithout DM. As compared with non-DM monkeys, DM monkeys had more cells that expressed KI-67 during progressionof acute kidney injury (AKI). Na+/K+ ATPase expression was clearly present at baseline in the basolateral tubular areas onlyin the non-DM monkeys. At 48 h, its expression in the basolateral area was not visible in DM monkeys, but was still presentin intercellular junctions of non-DM monkeys. The expression of TNF-α was higher in DM before and 48 h after ischemia.Before and 24 h after ischemia, the number of CD31-positive capillaries was not different between 2 groups, although morecollapsed vessels were found at in DM at 24 h. At 48 h, the number of capillaries was less in DM compared with those fromnon-DM animals. DM monkeys had more interstitial CD3-positive cells than did non-DM monkeys at 24 and 48 h afterischemia. Finally, FSP-1-stained cells were more abundant in DM than non-DM at 24 and 48 h. Our results show that DMaggravates the recovery of renal ischemia/reperfusion injury by affecting tubular proliferation, capillary density, T cell infiltrationand by altering protein and mRNA expression of various genes involved in ion channel, inflammation, and fibroticchange. The results from this observational study demonstrate that DM aggravates the recovery of renal ischemia/reperfusioninjury by affecting multiple events including tubular necrosis, proliferation, function, inflammation and by inducingcapillary rarefaction in cynomolgus monkeys.

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