Yu Jing, Gong Wei, Wu Yimei, Li Shuzhen, Cui Yiyun, Ma Yifei, Zhang Yue, Yang Guangrui, Huang Songming, Jia Zhanjun, Zhang Aihua
Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and Nanjing Key Laboratory of Pediatrics, Nanjing, China.
Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China; and Nanjing Key Laboratory of Pediatrics, Nanjing, China
Am J Physiol Renal Physiol. 2016 Mar 15;310(6):F492-8. doi: 10.1152/ajprenal.00499.2015. Epub 2016 Jan 6.
Podocyte damage is a common pathological feature in many types of glomerular diseases and is involved in the occurrence and progression of kidney disease. However, the pathogenic mechanisms leading to podocyte injury are still uncertain. The present study was undertaken to investigate the role of microsomal PGE synthase (mPGES)-1 in adriamycin (ADR)-induced podocyte injury as well as the underlying mechanism. In both mouse kidneys and in vitro podocytes, application of ADR remarkably enhanced mPGES-1 expression in line with a stimulation of cyclooxygenase-2. Interestingly, inhibition of mPGES-1 with a small interfering RNA approach significantly attenuated ADR-induced downregualtion of podocin and nephrin. Moreover, ADR-induced podocyte apoptosis was also markedly blocked in parallel with blunted caspase-3 induction. In agreement with the improvement of cell phenotypic alteration and apoptosis, the enhanced inflammatory markers of IL-1β and TNF-α were also significantly suppressed by mPGES-1 silencing. More importantly, in mPGES-1-deficient mice, albuminuria induced by ADR showed a remarkable attenuation in line with decreased urinary output of PGE2 and TNF-α, highly suggesting an in vivo role of mPGES-1 in mediating podocyte injury. In summary, findings from the present study offered the first evidence demonstrating a pathogenic role of mPGES-1 in mediating ADR-induced podocyte injury possibly via triggering an inflammatory response.
足细胞损伤是多种肾小球疾病常见的病理特征，并且参与了肾脏疾病的发生和进展。然而，导致足细胞损伤的致病机制仍不明确。本研究旨在探讨微粒体前列腺素E合酶（mPGES）-1在阿霉素（ADR）诱导的足细胞损伤中的作用及其潜在机制。在小鼠肾脏和体外培养的足细胞中，应用ADR均可显著增强mPGES-1的表达，同时伴有环氧化酶-2的激活。有趣的是，采用小干扰RNA方法抑制mPGES-1可显著减轻ADR诱导的足突蛋白和nephrin的下调。此外，ADR诱导的足细胞凋亡也明显受到抑制，同时caspase-3的诱导也减弱。与细胞表型改变和凋亡的改善相一致，mPGES-1沉默也显著抑制了白细胞介素-1β和肿瘤坏死因子-α等炎症标志物的升高。更重要的是，在mPGES-1基因敲除小鼠中，ADR诱导的蛋白尿明显减轻，同时前列腺素E2和肿瘤坏死因子-α的尿量排泄减少，这强烈提示mPGES-1在介导足细胞损伤中具有体内作用。总之，本研究结果首次证明了mPGES-1在介导ADR诱导的足细胞损伤中可能通过引发炎症反应而发挥致病作用。
