Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China.
Am J Physiol Renal Physiol. 2021 Mar 1;320(3):F454-F463. doi: 10.1152/ajprenal.00426.2020. Epub 2021 Feb 8.
Tumor necrosis factor (TNF)-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of mesenchymal stem cells (MSCs), but its ability to protect the ischemic kidney is unknown. In a swine model of renal artery stenosis (RAS) and metabolic syndrome (MetS), we assessed the contribution of TSG-6 produced by MSCs to their immunomodulatory properties. Pigs were studied after 16 wk of diet-induced MetS and unilateral RAS and were either untreated or treated 4 wk earlier with intrarenal autologous adipose tissue-derived MSCs ( = 6 each). Lean, MetS, and RAS sham animals served as controls. We studied renal function in vivo (using computed tomography) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were also measured in conditioned media of human MSCs incubated with TNF-α and levels of the tubular injury marker lactate dehydrogenase in conditioned media after coculturing macrophages with injured human kidney 2 (HK-2) cells with or without TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration were also determined. MetS + RAS showed increased M1 macrophages and renal vein TNF-α levels. After MSC delivery, renal vein TSG-6 increased and TNF-α decreased, the M1-to-M2 ratio decreased, renal function improved, and fibrosis was alleviated. In vitro, TNF-α increased TSG-6 secretion by human MSCs. TSG-6 decreased lactate dehydrogenase release from injured HK-2 cells, increased expression of macrophage M2 markers, and reduced M1 macrophage adhesion and migration. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype. These observations suggest that TSG-6 is endowed with renoprotective properties. Tumor necrosis factor-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.
肿瘤坏死因子（TNF）-α诱导的基因/蛋白（TSG）-6 调节间充质干细胞（MSCs）的免疫调节特性，但它保护缺血性肾脏的能力尚不清楚。在肾动脉狭窄（RAS）和代谢综合征（MetS）的猪模型中，我们评估了 MSC 产生的 TSG-6 对其免疫调节特性的贡献。在饮食诱导的 MetS 和单侧 RAS 后 16 周，猪接受了或未接受肾内自体脂肪组织衍生的 MSCs 治疗（每组 6 只）。瘦猪、MetS 和 RAS 假手术动物作为对照。我们在体内（使用计算机断层扫描）和肾脏组织病理学以及巨噬细胞表型方面研究了肾功能，并在体外测量了 TNF-α孵育的人 MSCs 条件培养基中的 TSG-6 水平以及与未用 TSG-6 共培养的受损人肾 2（HK-2）细胞与巨噬细胞共培养后条件培养基中的肾小管损伤标志物乳酸脱氢酶的水平。还确定了 TSG-6 对巨噬细胞表型（M1/M2）、黏附和迁移的影响。MetS+RAS 显示 M1 巨噬细胞增加和肾静脉 TNF-α水平升高。MSC 给药后，肾静脉 TSG-6 增加，TNF-α减少，M1 至 M2 比值降低，肾功能改善，纤维化减轻。在体外，TNF-α增加了人 MSCs 的 TSG-6 分泌。TSG-6 减少了受损 HK-2 细胞的乳酸脱氢酶释放，增加了巨噬细胞 M2 标志物的表达，并减少了 M1 巨噬细胞的黏附和迁移。因此，MSC 释放的 TSG-6 可能会减轻肾小管细胞损伤，这与调节巨噬细胞功能和表型有关。这些观察结果表明，TSG-6 具有肾脏保护特性。
