Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease.
Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease.
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DOI：
10.1172/jci156250
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发表时间：
2022-08-15
影响因子：
15.9
通讯作者：
Shankland, Stuart J.
中科院分区：
文献类型：
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作者：
Pippin, Jeffrey W.;Kaverina, Natalya;Wang, Yuliang;Eng, Diana G.;Zeng, Yuting;Tran, Uyen;Loretz, Carol J.;Chang, Anthony;Akilesh, Shreeram;Poudel, Chetan;Perry, Hannah S.;O'Connor, Christopher;Vaughan, Joshua C.;Bitzer, Markus;Wessely, Oliver;Shankland, Stuart J.
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。肾脏老化的机制还不是很清楚。我们先前的研究表明，从老年小鼠分离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。在显微解剖的人肾小球中，PDCD1转录随年龄增加而增加，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内膜/管腔比有关。在足细胞的体外研究表明，PD-1信号在细胞存活和诱导衰老相关的分泌表型中起着关键作用。为了证明PD-1信号在足细胞衰老中起关键作用，给老龄小鼠注射了抗PD-1抗体。治疗可明显改善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，但不能延长壁上皮细胞、系膜细胞或内皮细胞的寿命。转录和免疫组织化学研究表明，抗PD-1抗体处理提高了足细胞的健康寿命。给患有实验性局灶节段性肾小球硬化(FSGS)的幼鼠注射相同的抗PD-1抗体，可降低蛋白尿并改善足细胞数量。这些结果表明，PD-1信号的增加在肾脏和肝脏老化以及FSGS中起到了关键作用。
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.