With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

中文翻译：

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PD-1 信号上调会拮抗老年肾脏和疾病中的肾小球健康

随着人口老龄化，肾脏健康成为一个重要的医疗和社会经济因素。肾脏衰老机制尚不清楚。我们之前表明，从老年小鼠中分离出的足细胞表现出程序性细胞死亡蛋白 1 (PD-1) 表面受体及其 2 个配体（PD-L1 和 PD-L2）的表达增加。PDCD1在显微解剖的人肾小球中，转录本随着年龄的增长而增加，这与较低的估计肾小球滤过率和较高的节段性肾小球硬化和血管动脉内膜与管腔比率相关。足细胞的体外研究表明，PD-1 信号传导在细胞存活和诱导衰老相关分泌表型中发挥着关键作用。为了证明 PD-1 信号传导对于足细胞衰老至关重要，给老年小鼠注射了抗 PD-1 抗体。治疗显着改善了肾脏和肝脏的衰老表型。在肾小球中，它延长了足细胞的寿命，但不延长壁上皮细胞、系膜细胞或内皮细胞的寿命。转录组学和免疫组织化学研究表明，抗 PD-1 抗体治疗可改善足细胞的健康寿命。对患有实验性局灶节段性肾小球硬化症 (FSGS) 的年轻小鼠施用相同的抗 PD-1 抗体可降低蛋白尿并增加足细胞数量。这些结果表明，PD-1 信号传导的增加对肾脏和肝脏衰老以及 FSGS 具有重要贡献。