title: 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.
abstract: 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.
authors.affiliation: Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Institute of Clinical Medicine, Aarhus, Denmark.
authors.forename: Lea
authors.initials: L
authors.lastname: Pedersen
authors.affiliation: Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Institute of Clinical Medicine, Aarhus, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Wogensen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Cecchi
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Trine
authors.initials: T
authors.lastname: Dalsgaard
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnæs-Hansen
mesh_terms: D000740:Anemia / Q000209:etiology / Q000628:therapy*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy; D050533:Glomerular Basement Membrane / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D005353:Fibronectins; D006454:Hemoglobins; D053773:Transforming Growth Factor beta1; D004921:Erythropoietin; D003094:Collagen