Rodrigues Camila Eleuterio, Capcha José Manuel Condor, de Bragança Ana Carolina, Sanches Talita Rojas, Gouveia Priscila Queiroz, de Oliveira Patrícia Aparecida Ferreira, Malheiros Denise Maria Avancini Costa, Volpini Rildo Aparecido, Santinho Mirela Aparecida Rodrigues, Santana Bárbara Amélia Aparecida, Calado Rodrigo do Tocantins, Noronha Irene de Lourdes, Andrade Lúcia
Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
Department of Internal Medicine, Division of Haematology, University of São Paulo at Ribeirão Preto School of Medicine, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, Brazil.
Stem Cell Res Ther. 2017 Jan 28;8(1):19. doi: 10.1186/s13287-017-0475-8.
Mesenchymal stromal cells (MSCs) represent an option for the treatment of acute kidney injury (AKI). It is known that young stem cells are better than are aged stem cells at reducing the incidence of the senescent phenotype in the kidneys. The objective of this study was to determine whether AKI leads to premature, stress-induced senescence, as well as whether human umbilical cord-derived MSCs (huMSCs) can prevent ischaemia/reperfusion injury (IRI)-induced renal senescence in rats.
By clamping both renal arteries for 45 min, we induced IRI in male rats. Six hours later, some rats received 1 × 10 huMSCs or human adipose-derived MSCs (aMSCs) intraperitoneally. Rats were euthanised and studied on post-IRI days 2, 7 and 49.
On post-IRI day 2, the kidneys of huMSC-treated rats showed improved glomerular filtration, better tubular function and higher expression of aquaporin 2, as well as less macrophage infiltration. Senescence-related proteins (β-galactosidase, p21, p16 and transforming growth factor beta 1) and microRNAs (miR-29a and miR-34a) were overexpressed after IRI and subsequently downregulated by the treatment. The IRI-induced pro-oxidative state and reduction in Klotho expression were both reversed by the treatment. In comparison with huMSC treatment, the treatment with aMSCs improved renal function to a lesser degree, as well as resulting in a less pronounced increase in the renal expression of Klotho and manganese superoxide dismutase. Treatment with huMSCs ameliorated long-term kidney function after IRI, minimised renal fibrosis, decreased β-galactosidase expression and increased the expression of Klotho.
Our data demonstrate that huMSCs attenuate the inflammatory and oxidative stress responses occurring in AKI, as well as reducing the expression of senescence-related proteins and microRNAs. Our findings broaden perspectives for the treatment of AKI.
间充质基质细胞（MSCs）是治疗急性肾损伤（AKI）的一种选择。已知年轻干细胞在降低肾脏衰老表型发生率方面优于衰老干细胞。本研究的目的是确定AKI是否会导致过早的、应激诱导的衰老，以及人脐带间充质干细胞（huMSCs）是否能预防大鼠缺血/再灌注损伤（IRI）诱导的肾衰老。
通过夹闭双侧肾动脉45分钟，在雄性大鼠中诱导IRI。6小时后，部分大鼠腹腔注射1×10的huMSCs或人脂肪间充质干细胞（aMSCs）。在IRI后第2、7和49天对大鼠实施安乐死并进行研究。
在IRI后第2天，接受huMSCs治疗的大鼠肾脏显示肾小球滤过改善、肾小管功能更好、水通道蛋白2表达更高，以及巨噬细胞浸润更少。衰老相关蛋白（β-半乳糖苷酶、p21、p16和转化生长因子β1）和微小RNA（miR-29a和miR-34a）在IRI后过表达，随后经治疗下调。治疗逆转了IRI诱导的促氧化状态和Klotho表达降低。与huMSCs治疗相比，aMSCs治疗改善肾功能的程度较小，并且导致肾脏中Klotho和锰超氧化物歧化酶表达的增加不太明显。huMSCs治疗改善了IRI后的长期肾功能，使肾纤维化最小化，降低了β-半乳糖苷酶表达并增加了Klotho表达。
我们的数据表明，huMSCs减轻了AKI中发生的炎症和氧化应激反应，以及降低了衰老相关蛋白和微小RNA的表达。我们的研究结果拓宽了AKI治疗的前景。
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