Kane R, Stevenson L, Godson C, Stitt A W, O'Brien C
Institute of Ophthalmology, 60 Eccles Street, Dublin 7, Ireland.
Br J Ophthalmol. 2005 Dec;89(12):1638-42. doi: 10.1136/bjo.2005.069591.
To assess the influence of high extracellular glucose on the expression of the bone morphogenetic protein (BMP) antagonist, gremlin, in cultured bovine retinal pericytes (BRPC).
BRPC were cultured under conditions of 5 mM and 30 mM d-glucose for 7 days and total RNA was isolated. Gremlin mRNA levels were correlated, by RT-PCR, with other genes implicated in the pathogenesis of diabetic retinopathy and the signalling pathways in high glucose induced gremlin expression were probed using physiological inhibitors. Gremlin expression was also examined in the retina of streptozotocin induced diabetic mice.
High glucose stimulated a striking increase in BRPC gremlin mRNA levels in parallel with increases in mRNA for the growth factors vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFbeta), and connective tissue growth factor (CTGF) and changes in other genes including fibronectin and plasminogen activator inhibitor-1 (PAI-1). High glucose triggered gremlin expression was modulated by anti-TGFbeta antibody, by the uncoupler of oxidative phosphorylation, CCCP, and by inhibition of MAP-kinase (MAPK) activation. Striking gremlin expression was observed in the outer retina of diabetic mice and also at the level of the vascular wall.
Gremlin gene expression is induced in BRPC in response to elevated glucose and in the retina of the streptozotocin induced diabetic mouse. Its expression is modulated by hyperglycaemic induction of the MAPK, reactive oxygen species, and TGFbeta pathways, all of which are reported to have a role in diabetic fibrotic disease. This implicates a role for gremlin in the pathogenesis of diabetic retinopathy.
评估高细胞外葡萄糖对培养的牛视网膜周细胞（BRPC）中骨形态发生蛋白（BMP）拮抗剂gremlin表达的影响。
将BRPC在5 mM和30 mM d -葡萄糖条件下培养7天，然后分离总RNA。通过逆转录聚合酶链反应（RT - PCR）将gremlin mRNA水平与糖尿病视网膜病变发病机制中涉及的其他基因相关联，并使用生理抑制剂探究高糖诱导gremlin表达的信号通路。还在链脲佐菌素诱导的糖尿病小鼠视网膜中检测了gremlin的表达。
高糖刺激BRPC中gremlin mRNA水平显著增加，同时血管内皮生长因子（VEGF）、转化生长因子β（TGFβ）和结缔组织生长因子（CTGF）等生长因子的mRNA水平也增加，以及包括纤连蛋白和纤溶酶原激活物抑制剂 - 1（PAI - 1）在内的其他基因发生变化。高糖引发的gremlin表达受到抗TGFβ抗体、氧化磷酸化解偶联剂CCCP以及丝裂原活化蛋白激酶（MAPK）激活抑制的调节。在糖尿病小鼠的外视网膜以及血管壁水平观察到显著的gremlin表达。
在高糖环境下，BRPC以及链脲佐菌素诱导的糖尿病小鼠视网膜中gremlin基因表达被诱导。其表达受到MAPK、活性氧和TGFβ途径的高血糖诱导调节，所有这些途径都被报道在糖尿病纤维化疾病中起作用。这表明gremlin在糖尿病视网膜病变的发病机制中起作用。
