PGC-1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI
PGC-1α deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI
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DOI：
10.1002/path.5282
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发表时间：
2019-09-01
影响因子：
7.3
通讯作者：
Sanz, Ana B.
中科院分区：
文献类型：
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作者：
Fontecha-Barriuso, Miguel;Martin-Sanchez, Diego;Sanz, Ana B.
PGC-1 α（过氧化物酶体增殖物激活受体γ共激活因子-1 α， PPARGC1A）调节参与能量稳态和线粒体生物发生的基因的表达。在这里，我们确定了转录调节因子PGC-1 α的失活是实验性肾毒性急性肾损伤（AKI）的一个里程碑，并描述了PGC-1 α缺乏对肾损伤炎症和细胞死亡的体内后果。对叶酸诱导AKI的WT小鼠进行肾脏转录组学分析，发现1398个上调基因和1627个下调基因。上游转录调节因子分析指出，PGC-1 α作为转录因子可能驱动观察到的表达变化，其活性降低幅度最大。PGC-1 α表达降低与肾损伤相同。Ppargc1a（-/-）小鼠出现自发性亚临床肾损伤，其特征是小管间质炎症和Ngal表达增加。AKI后，Ppargc1a（-/-）小鼠的存活率较低，肾功能丧失、肾小管损伤更严重，肾脏中线粒体PGC-1 α依赖基因表达减少，线粒体质量比WT小鼠更早下降。此外，存活的Ppargc1a（-/-）小鼠显示出更高的小管细胞死亡率、代偿性增殖、促炎细胞因子表达、nf - κ B激活和间质炎性细胞浸润率。具体来说，Ppargc1a（-/-）小鼠表现出M1增加、M2反应减少以及抗炎细胞因子IL-10的表达。在培养的肾小管细胞中，PGC-1 α靶向促进自发细胞死亡和促炎反应。综上所述，PGC-1 α失活是肾毒性AKI中基因表达反应的关键驱动因素，PGC-1 α缺乏可促进自发性炎症性肾脏反应，该反应在AKI期间被放大。(c) 2019年大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC-1 alpha as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the in vivo consequences of PGC-1 alpha deficiency over inflammation and cell death in kidney injury. Kidney transcriptomic analyses of WT mice with folic acid-induced AKI revealed 1398 up- and 1627 downregulated genes. Upstream transcriptional regulator analyses pointed to PGC-1 alpha as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC-1 alpha expression was shared by human kidney injury. Ppargc1a(-/-) mice had spontaneous subclinical kidney injury characterized by tubulointerstitial inflammation and increased Ngal expression. Upon AKI, Ppargc1a(-/-) mice had lower survival and more severe loss of renal function, tubular injury, and reduction in expression of mitochondrial PGC-1 alpha-dependent genes in the kidney, and an earlier decrease in mitochondrial mass than WT mice. Additionally, surviving Ppargc1a(-/-) mice showed higher rates of tubular cell death, compensatory proliferation, expression of proinflammatory cytokines, NF-kappa B activation, and interstitial inflammatory cell infiltration. Specifically, Ppargc1a(-/-) mice displayed increased M1 and decreased M2 responses and expression of the anti-inflammatory cytokine IL-10. In cultured renal tubular cells, PGC-1 alpha targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC-1 alpha inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC-1 alpha deficiency promotes a spontaneous inflammatory kidney response that is magnified during AKI. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.