Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy.
Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy.
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Optineurin介导的线粒体自噬保护糖尿病肾病肾小管上皮细胞免于加速衰老
DOI：
10.1038/s41419-017-0127-z
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发表时间：
2018-01-24
影响因子：
9
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Chen K;Dai H;Yuan J;Chen J;Lin L;Zhang W;Wang L;Zhang J;Li K;He Y
早衰是糖尿病肾病（DN）进展的关键过程。DN时肾小管上皮细胞（RTEC）的早衰可能是由于受损线粒体的积累。线粒体自噬是通过PTEN诱导的推定激酶1（PINK 1）介导的视神经磷酸酶（OPTN）向线粒体募集来消除受损线粒体的主要过程。我们的目的是研究OPTN参与DN背景下RTEC细胞衰老的线粒体自噬调节。在体外，小鼠RTECs在30 mM高糖（HG）条件下培养48 h后，衰老标志物P16、P21、DcR 2、SA-β-gal、SAHF和线粒体吞噬降解不足标志物（线粒体P62）的表达增加。线粒体分裂/线粒体自噬抑制剂Mdivi-1显著增强高糖条件下RTEC的衰老，而自噬/线粒体自噬激动剂Torin 1抑制细胞衰老。MitoTempo在有或没有Mdivi-1的情况下抑制HG诱导的线粒体活性氧和细胞衰老。HG刺激后，线粒体吞噬体形成的两个调节因子PINK 1和OPTN的表达显著降低。在HG条件下，PINK 1的过表达没有增强线粒体吞噬体的形成。OPTN沉默显著抑制HG诱导的线粒体自噬体形成，OPTN过表达通过促进线粒体自噬缓解细胞衰老。在临床标本中，随着肾小管间质损伤评分的增加，肾脏OPTN表达逐渐降低。OPTN阳性肾小管细胞不表达衰老标志物P16。OPTN表达与血清肌酐水平呈负相关，与eGFR呈正相关。因此，OPTN介导的线粒体自噬在DN中HG诱导的RTEC衰老中起着至关重要的调节作用。因此，OPTN可能是DN中一种潜在的抗衰老因子。
Premature senescence is a key process in the progression of diabetic nephropathy (DN). Premature senescence of renal tubular epithelial cells (RTEC) in DN may result from the accumulation of damaged mitochondria. Mitophagy is the principal process that eliminates damaged mitochondria through PTEN-induced putative kinase 1 (PINK1)-mediated recruitment of optineurin (OPTN) to mitochondria. We aimed to examine the involvement of OPTN in mitophagy regulation of cellular senescence in RTEC in the context of DN. In vitro, the expression of senescence markers P16, P21, DcR2, SA-β-gal, SAHF, and insufficient mitophagic degradation marker (mitochondrial P62) in mouse RTECs increased after culture in 30 mM high-glucose (HG) conditions for 48 h. Mitochondrial fission/mitophagy inhibitor Mdivi-1 significantly enhanced RTEC senescence under HG conditions, whereas autophagy/mitophagy agonist Torin1 inhibited cell senescence. MitoTempo inhibited HG-induced mitochondrial reactive oxygen species and cell senescence with or without Mdivi-1. The expression of PINK1 and OPTN, two regulatory factors for mitophagosome formation, decreased significantly after HG stimulation. Overexpression of PINK1 did not enhance mitophagosome formation under HG conditions. OPTN silencing significantly inhibited HG-induced mitophagosome formation, and overexpression of OPTN relieved cellular senescence through promoting mitophagy. In clinical specimens, renal OPTN expression was gradually decreased with increased tubulointerstitial injury scores. OPTN-positive renal tubular cells did not express senescence marker P16. OPTN expression also negatively correlated with serum creatinine levels, and positively correlated with eGFR. Thus, OPTN-mediated mitophagy plays a crucial regulatory role in HG-induced RTEC senescence in DN. OPTN may, therefore, be a potential antisenescence factor in DN.
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