GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure.
GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure.
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DOI：
10.1016/j.surg.2018.03.008
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发表时间：
2018-08
期刊：
影响因子：
3.8
通讯作者：
Zimmers TA
中科院分区：
文献类型：
--
作者：
Pons M;Koniaris LG;Moe SM;Gutierrez JC;Esquela-Kerscher A;Zimmers TA
GDF 11调节胚胎模式和肾器官发生。在此，我们试图定义GDF 11在成人肾脏和肾脏疾病中的功能。检查了体外肾细胞系、遗传和小鼠体内肾损伤模型。在测试的组织中，Gdf 11在正常成年小鼠肾脏中最高。表达在5/6肾切除（5/6 Nx）、缺血再灌注损伤、卡那霉素中毒或单侧输尿管梗阻（UUO）后急性增加。在成年小鼠中全身给予高剂量GDF 11导致肾衰竭，伴随肾萎缩、间质纤维化、肾小管细胞的上皮细胞向间质细胞转化（EMT），并最终死亡。这些作用与SMAD 2的磷酸化有关，并可被Follistatin阻断。相反，Gdf 11杂合子小鼠在基线和UUO后与野生型同窝小鼠相比，肾Gdf 11表达、肾纤维化和纤维化相关基因表达均降低。GDF 11剂量调节的肾脏特异性后果是对肾细胞的直接影响。GDFll诱导NRK 49 f肾成纤维细胞的增殖和活化，并且还以SMAD 3依赖性方式促进顶CD-3肾小管上皮细胞的EMT。总之，这些数据表明，GDF 11及其下游信号是肾损伤的体内关键介质。这些作用是通过GDF 11对肾小管细胞和成纤维细胞的直接作用。因此，GDF 11的调节为涉及肾纤维化和肾小管功能受损的疾病提供了治疗靶点。
GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases. In vitro renal cell lines, genetic and murine in vivo renal injury models were examined. Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely following 5/6 nephrectomy (5/6Nx), ischemia-reperfusion injury, kanamycin toxicity or unilateral ureteric obstruction (UUO). Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition (EMT) of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by Follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis and expression of fibrosis-associated genes both at baseline and after UUO compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted EMT of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner. Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function.
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影响因子：
29
作者：
Egerman MA;Cadena SM;Gilbert JA;Meyer A;Nelson HN;Swalley SE;Mallozzi C;Jacobi C;Jennings LL;Clay I;Laurent G;Ma S;Brachat S;Lach-Trifilieff E;Shavlakadze T;Trendelenburg AU;Brack AS;Glass DJ
通讯作者：
Glass DJ
影响因子：
13.6
作者：
Ishani, Areef;Xue, Jay L.;Collins, Allan J.
通讯作者：
Collins, Allan J.
DOI：
10.1152/ajprenal.00326.2007
发表时间：
2008-05-01
影响因子：
4.2
作者：
Ivanova, Larissa;Butt, Michael J.;Matsell, Douglas G.
通讯作者：
Matsell, Douglas G.
影响因子：
3.6
作者：
Jinnin, M;Ihn, H;Tamaki, K
通讯作者：
Tamaki, K
影响因子：
2.5
作者：
Dichmann, Darwin S.;Yassin, Hani;Serup, Palle
通讯作者：
Serup, Palle