Reduction in podocyte SIRT1 accelerates kidney injury in aging mice
Reduction in podocyte SIRT1 accelerates kidney injury in aging mice
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DOI：
10.1152/ajprenal.00255.2017
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发表时间：
2017-09-01
影响因子：
4.2
通讯作者：
Lee, Kyung
中科院分区：
文献类型：
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作者：
Chuang, Peter Y.;Cai, Weijing;Lee, Kyung
老年人群中慢性肾脏疾病的发病率和患病率均呈上升趋势。虽然已知衰老会引起肾损伤，但其潜在的分子机制仍不清楚。Sirtuin 1（Sirt 1）是一种长寿基因，已知可保护肾细胞免受各种细胞应激的损伤。在以前的研究中，我们发现足细胞特异性Sirt 1的缺失加重了糖尿病肾损伤。然而，Sirt 1在衰老诱导的足细胞损伤中的作用尚不清楚。因此，在这项研究中，我们试图确定足细胞特异性减少Sirt 1在年龄诱导的肾损伤中的作用。我们使用了表达针对Sirt 1的shRNA的可诱导足细胞特异性Sirt 1敲除小鼠（Pod-Sirt 1（RNAi））和表达针对荧光素酶的shRNA的对照小鼠（Pod-Luci（RNAi））。我们发现，足细胞Sirt 1的减少导致加重衰老诱导的肾小球硬化和蛋白尿。此外，与老年Pod-Luci（RNAi）小鼠相比，老年Pod-Sirt 1（RNAi）小鼠中氧化应激标志物8-羟基-2 '-脱氧鸟苷（8-OHdG）的尿水平显著增加。尽管与年轻对照组相比，老年小鼠的足细胞特异性标记物减少，但与Pod-Luci（RNAi）小鼠相比，老年Pod-Sirt 1（RNAi）小鼠的减少进一步加剧。有趣的是，细胞衰老标记物的表达在Pod-Sirt 1（RNAi）小鼠的肾小球中显著高于Pod-Luci（RNAi）小鼠，这表明细胞衰老可能导致衰老肾脏中的足细胞损失。最后，我们证实了Pod-Sirt 1（RNAi）肾小球通过SIRT 1介导的去乙酰化作用与转录因子过氧化物酶体增殖物激活受体（PPAR）-α共激活因子-1（PGC 1 α）/PPAR γ、叉头盒O（FOXO）3、FOXO 4和p65 NF-κ B B的激活减少有关。总之，我们的数据表明SIRT 1可能是治疗衰老相关肾病患者的潜在治疗靶点。
Both the incidence and prevalence of chronic kidney disease are increasing in the elderly population. Although aging is known to induce kidney injury, the underlying molecular mechanisms remain unclear. Sirtuin 1 (Sirt1), a longevity gene, is known to protect kidney cell injury from various cellular stresses. In previous studies, we showed that the podocyte-specific loss of Sirt1 aggravates diabetic kidney injury. However, the role of Sirt1 in aging-induced podocyte injury is not known. Therefore, in this study we sought to determine the effects of podocyte-specific reduction of Sirt1 in age-induced kidney injury. We employed the inducible podocyte-specific Sirt1 knockdown mice that express shRNA against Sirt1 (Pod-Sirt1(RNAi)) and control mice that express shRNA for luciferase (Pod-Luci(RNAi)). We found that reduction of podocyte Sirt1 led to aggravated aging-induced glomerulosclerosis and albuminuria. In addition, urinary level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, was markedly increased in aged Pod-Sirt1(RNAi) mice compared with aged Pod-Luci(RNAi) mice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-Sirt1(RNAi) compared with Pod-Luci(RNAi) mice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-Sirt1(RNAi) mice than Pod-Luci(RNAi) mice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-Sirt1(RNAi) glomeruli were associated with reduced activation of the transcription factors peroxisome proliferator-activated receptor (PPAR)-alpha coactivador-1 (PGC1 alpha)/PPAR gamma, forkhead box O (FOXO)3, FOXO4, and p65 NF-kappa B, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease.