Rap1 ameliorates renal tubular injury in diabetic nephropathy.
Rap1 ameliorates renal tubular injury in diabetic nephropathy.
复制标题
Rap1 改善糖尿病肾病的肾小管损伤
作者：
Xiao L;Zhu X;Yang S;Liu F;Zhou Z;Zhan M;Xie P;Zhang D;Li J;Song P;Kanwar YS;Sun L
Rap1b改善高糖（HG）诱导的小管细胞线粒体功能障碍。然而，其在体内糖尿病肾病（DN）中的作用和确切机制尚不清楚。我们假设Rap1主要通过调节线粒体来源的氧化应激在DN的小管损伤中起保护作用。利用超声微泡介导技术，研究Rap1b在链脲唑菌素（STZ）诱导的糖尿病大鼠以及暴露于HG环境下的肾近端上皮小管细胞系（HK-2）中线粒体功能障碍和DN小管细胞中的作用和确切机制。结果显示，在DN患者肾活检的小管中，Rap1b的表达显著降低。过表达组成活性Rap1b G12V可显著改善stz诱导大鼠肾小管线粒体功能障碍、氧化应激和凋亡，并伴有转录因子C/EBP-β和PGC-1α的表达增加。此外，Rap1b G12V还降低了HG诱导的HK-2细胞中线粒体裂变蛋白Drp-1的磷酸化水平，同时提高了线粒体生物发生相关基因和抗氧化剂的表达。转染C/EBP-β或PGC-1α短干扰RNA可以模拟这些作用。此外，Rap1b可以调节C/EBP-β与内源性PGC-1α启动子的结合以及PGC-1α与过氧化氢酶或线粒体超氧化物歧化酶的相互作用，表明Rap1b通过C/EBP-β - PGC-1α信号通路调节线粒体功能障碍，改善小管损伤，减缓DN的进展。
Rap1b ameliorates high glucose (HG)-induced mitochondrial dysfunction in tubular cells. However, its role and precise mechanism in diabetic nephropathy (DN) in vivo remain unclear. We hypothesize that Rap1 plays a protective role in tubular damage of DN by modulating primarily the mitochondria-derived oxidative stress. The role and precise mechanisms of Rap1b on mitochondrial dysfunction and of tubular cells in DN were examined in rats with streptozotocin (STZ)-induced diabetes that have Rap1b gene transfer using an ultrasound microbubble-mediated technique as well as in renal proximal epithelial tubular cell line (HK-2) exposed to HG ambiance. The results showed that Rap1b expression decreased significantly in tubules of renal biopsies from patients with DN. Overexpression of a constitutively active Rap1b G12V notably ameliorated renal tubular mitochondrial dysfunction, oxidative stress, and apoptosis in the kidneys of STZ-induced rats, which was accompanied with increased expression of transcription factor C/EBP-β and PGC-1α. Furthermore, Rap1b G12V also decreased phosphorylation of Drp-1, a key mitochondrial fission protein, while boosting the expression of genes related to mitochondrial biogenesis and antioxidants in HK-2 cells induced by HG. These effects were imitated by transfection with C/EBP-β or PGC-1α short interfering RNA. In addition, Rap1b could modulate C/EBP-β binding to the endogenous PGC-1α promoter and the interaction between PGC-1α and catalase or mitochondrial superoxide dismutase, indicating that Rap1b ameliorates tubular injury and slows the progression of DN by modulation of mitochondrial dysfunction via C/EBP-β–PGC-1α signaling.
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DOI：
10.1073/pnas.1032913100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Patti, ME;Butte, AJ;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
11.4
作者：
Baixauli, Francesc;Martin-Cofreces, Noa B.;Sanchez-Madrid, Francisco
通讯作者：
Sanchez-Madrid, Francisco
影响因子：
5.6
作者：
Chen SD;Yang DI;Lin TK;Shaw FZ;Liou CW;Chuang YC
通讯作者：
Chuang YC
影响因子：
4.8
作者：
Bouschet, T;Perez, V;Journot, L
通讯作者：
Journot, L
DOI：
10.1073/pnas.0611079104
发表时间：
2007-02-13
影响因子：
11.1
作者：
Haruna, Yoshisuke;Kashihara, Naoki;Kanwar, Yashpal S.
通讯作者：
Kanwar, Yashpal S.