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首页> 美国卫生研究院文献>other >Restoration of Haemoglobin Level Using Hydrodynamic Gene Therapy with Erythropoietin Does Not Alleviate the Disease Progression in an Anaemic Mouse Model for TGFβ1-Induced Chronic Kidney Disease
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Restoration of Haemoglobin Level Using Hydrodynamic Gene Therapy with Erythropoietin Does Not Alleviate the Disease Progression in an Anaemic Mouse Model for TGFβ1-Induced Chronic Kidney Disease

机译：使用促红细胞生成素的水动力基因疗法恢复血红蛋白水平不能缓解TGFβ1引起的慢性肾脏病的贫血小鼠模型中疾病的进展

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Erythropoietin, Epo, is a 30.4 kDa glycoprotein hormone produced primarily by the fetal liver and the adult kidney. Epo exerts its haematopoietic effects by stimulating the proliferation and differentiation of erythrocytes with subsequent improved tissue oxygenation. Epo receptors are furthermore expressed in non-haematopoietic tissue and today, Epo is recognised as a cytokine with many pleiotropic effects. We hypothesize that hydrodynamic gene therapy with Epo can restore haemoglobin levels in anaemic transgenic mice and that this will attenuate the extracellular matrix accumulation in the kidneys. The experiment is conducted by hydrodynamic gene transfer of a plasmid encoding murine Epo in a transgenic mouse model that overexpresses TGF-β1 locally in the kidneys. This model develops anaemia due to chronic kidney disease characterised by thickening of the glomerular basement membrane, deposition of mesangial matrix and mild interstitial fibrosis. A group of age matched wildtype littermates are treated accordingly. After a single hydrodynamic administration of plasmid DNA containing murine EPO gene, sustained high haemoglobin levels are observed in both transgenic and wildtype mice from 7.5 ± 0.6 mmol/L to 9.4 ± 1.2 mmol/L and 10.7 ± 0.3 mmol/L to 15.5 ± 0.5 mmol/L, respectively. We did not observe any effects in the thickness of glomerular or tubular basement membrane, on the expression of different collagen types in the kidneys or in kidney function after prolonged treatment with Epo. Thus, Epo treatment in this model of chronic kidney disease normalises haemoglobin levels but has no effect on kidney fibrosis or function.
机译：促红细胞生成素Epo是一种30.4 kDa的糖蛋白激素，主要由胎儿肝脏和成年肾脏产生。 Epo通过刺激红细胞的增殖和分化以及随后改善的组织氧合作用发挥其造血作用。此外，Epo受体在非造血组织中表达，如今，Epo被认为是具有许多多效作用的细胞因子。我们假设Epo的水动力基因疗法可以恢复贫血转基因小鼠的血红蛋白水平，并且这将减弱肾脏中细胞外基质的积累。该实验是通过在小鼠肾脏中局部过度表达TGF-β1的转基因小鼠模型中通过编码鼠Epo的质粒的流体动力学基因转移来进行的。由于慢性肾脏疾病，该模型发展为贫血，其特征在于肾小球基底膜增厚，肾小球系膜基质沉积和轻度间质纤维化。一组年龄匹配的野生型同窝幼仔得到相应治疗。一次对含有鼠EPO基因的质粒DNA进行流体动力学给药后，在转基因和野生型小鼠中均观察到持续的高血红蛋白水平，从7.5±0.6 mmol / L到9.4±1.2 mmol / L和10.7±0.3 mmol / L到15.5±0.5分别为mmol / L。长期使用Epo治疗后，我们未观察到肾小球或肾小管基底膜厚度，肾脏中不同胶原蛋白类型的表达或肾功能的任何影响。因此，在这种慢性肾脏疾病模型中，Epo治疗可使血红蛋白水平正常化，但对肾脏纤维化或功能没有影响。

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