title: Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice.
abstract: VEGF is recognized as a major mediator in the development of diabetic nephropathy. Soluble Flt-1 (sFlt-1) is the endogenous inhibitor of VEGF, and recently genetic overexpression of sFlt-1 in the podocyte was shown to be protective in murine diabetic nephropathy. In this study, we performed a translational study to determine whether an intramuscular gene transfer of sFlt-1 can prevent the progression of renal disease in diabetic db/db mice. Adeno-associated virus-1 (AAV1) encoding human sFlt-1 in two different doses was intramuscularly administrated in db/db and wild-type mice. The sFlt-1-AAV1 treatment significantly increased serum sFlt-1 level at 4 and 8 wk. A dose that was developed in this study caused minimal abnormalities in normal mice but reduced albuminuria in diabetic db/db mice. In renal histology, sFlt-1 treatment at this dose had minimal effects on mesangial expansion in diabetic mice, whereas podocyte injury was significantly improved, at 8 wk. Unfortunately, tubulointerstitial injury was markedly exacerbated by sFlt-1 treatment in association with a reduction in endogenous VEGF expression and peritubular capillary loss. In conclusion, gene therapy with sFlt-1-AAV1 protects podocytes but accelerates tubulointerstitial injury in diabetic db/db mice. These data suggest systemic overexpression of sFlt-1 will not likely be useful for treating diabetic nephropathy.
authors.affiliation: Division of Nephrology, University of Florida, Gainesville, Florida, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakayama
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Maria
authors.initials: M
authors.lastname: Grant
authors.forename: Byron P
authors.initials: BP
authors.lastname: Croker
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors; D006801:Humans; D007273:Injections, Intramuscular; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000097:blood / Q000652:urine; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003094:Collagen; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1