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

29 Scopus citations

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)
Pages (from-to)F609-F616
JournalAmerican Journal of Physiology - Renal Physiology
Volume298
Issue number3
DOIs
StatePublished - Mar 1 2010

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Urology

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    Kosugi, T., Nakayama, T., Li, Q., Chiodo, V. A., Zhang, L., Campbell-Thompson, M., Grant, M., Croker, B. P., & Nakagawa, T. (2010). Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice. American Journal of Physiology - Renal Physiology, 298(3), F609-F616. https://doi.org/10.1152/ajprenal.00377.2009