Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.
Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.
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小鼠和人狭窄肾细胞衰老增加：间充质干细胞的作用。
DOI：
10.1002/jcp.29940
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发表时间：
2021-03
影响因子：
5.6
通讯作者：
Lerman LO
中科院分区：
文献类型：
--
作者：
Kim SR;Zou X;Tang H;Puranik AS;Abumoawad AM;Zhu XY;Hickson LJ;Tchkonia T;Textor SC;Kirkland JL;Lerman LO
细胞应激可引起无法克服的生长停滞，这被定义为细胞衰老。肾动脉狭窄（RAS）引起的狭窄肾（STK）缺血和损伤可能与细胞衰老有关。间充质干细胞（MSC）减少某些形式的STK损伤，但其逆转RAS衰老的能力仍不清楚。我们假设RAS引起STK衰老，而MSC可以改善这种衰老。在4周的RAS、2周前用脂肪组织来源的MSC处理的RAS或假手术后研究小鼠。测定STK衰老相关的β-半乳糖苷酶（SA-β-Gal）活性。蛋白质和基因表达被用来评估衰老和衰老相关的分泌表型（SASP），以及肾脏纤维化、炎症和毛细血管密度的染色。此外，在肾血管性高血压（RVH）患者中，在没有自体脂肪组织来源的MSC递送或递送后3个月，以及在健康志愿者（HV）中，衰老被评估为p16+和p21+尿外泌体。在RAS小鼠中，STK SA-β-Gal活性增加，衰老和SASP标记物表达显著升高。MSC改善肾功能、纤维化、炎症和毛细血管密度，并减弱SA-β-Gal活性，但大多数衰老和SASP水平保持不变。相应地，在人RVH中，与HV相比，p21+尿外泌体升高，MSC仅略微改善，而p16+外泌体保持不变。因此，RAS触发小鼠和人类受试者的肾衰老。骨髓间充质干细胞可减轻肾损伤，但仅部分减轻肾脏衰老。这些观察结果支持RAS靶向衰老清除治疗的探索。
Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue-derived MSCs 2 weeks earlier, or sham. STK senescence-associated β-galactosidase (SA-β-Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence-associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. Additionally, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue-derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA-β-Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA-β-Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.
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影响因子：
7.5
作者：
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通讯作者：
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影响因子：
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5.2
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Lerman, Lilach O.
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影响因子：
7.5
作者：
Rodrigues CE;Capcha JM;de Bragança AC;Sanches TR;Gouveia PQ;de Oliveira PA;Malheiros DM;Volpini RA;Santinho MA;Santana BA;Calado RD;Noronha IL;Andrade L
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Andrade L