Gremlin Aggravates Hyperglycemia-Induced Podocyte Injury by a TGFβ/Smad Dependent Signaling Pathway
Gremlin Aggravates Hyperglycemia-Induced Podocyte Injury by a TGFβ/Smad Dependent Signaling Pathway
复制标题
DOI：
10.1002/jcb.24559
复制
发表时间：
2013-09-01
影响因子：
4
通讯作者：
Shan, Tieying
中科院分区：
文献类型：
--
作者：
Li, Guiying;Li, Ying;Shan, Tieying
Gremlin是一种骨形态发生蛋白（BMP）拮抗剂，在糖尿病肾组织中升高。在糖尿病肾病（DN）的早期，足细胞受到损伤.研究了高血糖环境下培养的小鼠足细胞中gremlin蛋白和基因的表达。确定了gremlin在足细胞损伤中的作用和可能涉及的信号通路。通过共聚焦显微镜观察gremlin的表达。重组小鼠gremlin和针对gremlin 1的小干扰RNA（siRNA）鉴定了gremlin对足细胞的作用。对经典（smad 2/3）和非经典（p38 MAPK和JNK 1/2）转化生长因子β（TGF）/smad介导的信号转导的研究揭示了所涉及的假定的信号转导机制。Smad 2/3 siRNA和TGF受体抑制（SB 431542）用于探测gremlin诱导的足细胞损伤中的典型TGF/smad信号传导。TUNEL法检测足细胞凋亡。Gremlin在高糖培养的小鼠足细胞中表达增强，并且主要定位于细胞质中，而在细胞膜上可忽略不计。gremlin处理后nephrin和synaptopodin的表达下降，而且synaptopodin重排和nephrin重新定位明显。通过siRNA敲低gremlin 1或smad 2/3以及抑制TGFR（SB 431542）减轻足细胞损伤。抑制经典的TGF-β信号阻断gremlin对足细胞的损伤。总之，gremlin在高葡萄糖培养的小鼠足细胞中明显升高，并且可能利用内源性经典TGF 1/Smad信号传导来诱导足细胞损伤。通过siRNA敲低gremlin 1可能在减轻足细胞损伤方面具有临床意义。J.细胞。114：2101-2113，2013. (c)2013 Wiley Periodicals，Inc.
Gremlin is a bone morphogenic protein (BMP) antagonist and is elevated in diabetic kidney tissues. In the early course of diabetic nephropathy (DN), podocyte are injured. We studied the protein and gene expression of gremlin in mice podocytes cultured in hyperglycemia ambient. The role of gremlin on podocyte injury and the likely signaling pathways involved were determined. Expression of gremlin was visualized by confocal microscopy. Recombinant mouse gremlin and small interfering RNA (siRNA) targeting to gremlin1 identified the role played by gremlin on podocytes. Study of canonical (smad2/3) and non-canonical (p38MAPK and JNK1/2) transforming growth factor beta (TGF)/smad mediated signaling revealed the putative signaling mechanisms involved. Smad2/3 siRNA and TGF receptor inhibition (SB431542) were used to probe canonical TGF/smad signaling in gremlin-induced podocyte injury. Apoptosis of podocytes was measured by TUNEL assay. Gremlin expression was enhanced in high glucose cultured mouse podocytes, and was localized predominantly in the cytoplasm and negligibly on the cell membrane. Not only expression of nephrin and synaptopodin were decreased on treatment with gremlin, but also synaptopodin rearrangement and nephrin relocalization were evident. Knockdown gremlin1 or smad2/3 by siRNA, and inhibition of TGFR (SB431542) attenuated podocyte injury. Inhibition of canonical TGF- signal blocked the injury of gremlin on podocytes. In conclusion, gremlin was clearly elevated in high glucose cultured mouse podocytes, and likely employed endogenous canonical TGF1/Smad signaling to induce podocyte injury. Knockdown gremlin1 by siRNA may be clinically useful in the attenuation of podocyte injury. J. Cell. Biochem. 114: 2101-2113, 2013. (c) 2013 Wiley Periodicals, Inc.