Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice

Tomoki Kosugi, Takahiro Nakayama, Qiuhong Li, Vince A. Chiodo, Li Zhang, Martha Campbell-Thompson, Maria Grant, Byron P. Croker, Takahiko Nakagawa

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

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Albuminuria
Genetic Therapy
Podocytes
Dependovirus
Wounds and Injuries
Diabetic Nephropathies
Vascular Endothelial Growth Factor A
Kidney
Disease Progression
Histology
Therapeutics
Serum
Genes

Keywords

  • Adeno-associated virus serotype 1
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice. / Kosugi, Tomoki; Nakayama, Takahiro; Li, Qiuhong; Chiodo, Vince A.; Zhang, Li; Campbell-Thompson, Martha; Grant, Maria; Croker, Byron P.; Nakagawa, Takahiko.

In: American Journal of Physiology - Renal Physiology, Vol. 298, No. 3, 03.2010.

Research output: Contribution to journalArticle

Kosugi, T, Nakayama, T, Li, Q, Chiodo, VA, Zhang, L, Campbell-Thompson, M, Grant, M, Croker, BP & Nakagawa, T 2010, 'Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice', American Journal of Physiology - Renal Physiology, vol. 298, no. 3. https://doi.org/10.1152/ajprenal.00377.2009
Kosugi, Tomoki ; Nakayama, Takahiro ; Li, Qiuhong ; Chiodo, Vince A. ; Zhang, Li ; Campbell-Thompson, Martha ; Grant, Maria ; Croker, Byron P. ; Nakagawa, Takahiko. / Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice. In: American Journal of Physiology - Renal Physiology. 2010 ; Vol. 298, No. 3.
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