title: Long-term gene therapy with thrombospondin 2 inhibits TGF-β activation, inflammation and angiogenesis in chronic allograft nephropathy.
abstract: We recently identified Thrombospondin-2 (TSP-2) as a regulator of matrix remodelling and inflammation in experimental kidney disease by using TSP-2 null mice and successfully proved TSP-2 overexpression as a therapeutic concept in a short term glomerulonephritis model in the rat. In this current study, we investigated if long-term TSP-2 overexpression is also capable to ameliorate the progression of chronic kidney disease in the setting of the chronic allograft nephropathy F344-Lewis model in the rat. Two weeks after renal transplantation, two rat thigh muscles were transfected once only with either a TSP-2 overexpressing plasmid (n = 8) or a luciferase-expressing plasmid as control (n = 8). Rats were monitored for renal function, histological changes and gene expression in the graft for up to 30 weeks after transplantation. Unexpectedly, only in the TSP-2 treated group 2 rats died before the end of the experiment and renal function tended to be worsened in the TSP-2 group compared to the luciferase-treated controls. In addition, glomerular sclerosis and tubular interstitial injury as well as cortical fibronectin deposition was significantly increased in the TSP-2 treated kidneys despite reduced TGF-β activation and marked anti-inflammatory (macrophages, T-cells and B-cells) effects in this group. Long-term TSP-2 therapy impaired repair of renal endothelium, as demonstrated by significant higher glomerular and peritubular endothelial rarefaction and reduced endothelial cell proliferation in the transplanted kidneys from TSP-2 treated rats compared to controls. This TSP-2 effect was associated with decreased levels of renal VEGF but not VEGF1 receptor. In conclusion, despite its anti-inflammatory and TGF-β activation blocking effects, TSP-2 gene therapy did not ameliorate but rather worsened experimental chronic allograft nephropathy most likely via its anti-angiogenic properties on the renal microvasculature.
authors.affiliation: Department of Pathology, Nephropathology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Vogelbacher
authors.affiliation: Department of Pathology, Nephropathology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stief
authors.affiliation: Department of Pathology, Nephropathology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Grigo
authors.affiliation: Division of Nephrology, Medical Clinic III, University of Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hugo
mesh_terms: D064591:Allografts; D000818:Animals; D002460:Cell Line; D015316:Genetic Therapy / Q000379:methods*; D007249:Inflammation / Q000628:therapy; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016030:Kidney Transplantation / Q000009:adverse effects*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D019699:Thrombospondins / Q000235:genetics*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics; D000099262:Thrombospondin 2
chemical_list: D019699:Thrombospondins; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D000099262:Thrombospondin 2