Selective stimulation of VEGFR2 accelerates progressive renal disease

Waichi Sato, Katsuyuki Tanabe, Tomoki Kosugi, Kelly Hudkins, Miguel A. Lanaspa, Li Zhang, Martha Campbell-Thompson, Qiuhong Li, David A. Long, Charles E. Alpers, Takahiko Nakagawa

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


Vascular endothelial growth factor A (VEGF-A) can play both beneficial and deleterious roles in renal diseases, where its specific function might be determined by nitric oxide bioavailability. The complexity of VEGF-A in renal disease could in part be accounted for by the distinct roles of its two receptors; VEGFR1 is involved in the inflammatory responses, whereas VEGFR2 predominantly mediates angiogenesis. Because nondiabetic chronic renal disease is associated with capillary loss, we hypothesized that selective stimulation of VEGFR2 could be beneficial in this setting. However, VEGFR2 activation may be deleterious in the presence of nitric oxide deficiency. We systematically overexpressed a mutant form of VEGF-A binding only VEGFR2 (Flk-sel) using an adeno-associated virus-1 vector in wild-type and eNOS knockout mice and then induced renal injury by uninephrectomy. Flk-sel treatment increased angiogenesis and lowered blood pressure in both mouse types. Flk-sel overexpression caused mesangial injury with increased proliferation associated with elevated expression of PDGF, PDGF-β receptor, and VEGFR2; this effect was greater in eNOS knockout than in wild-type mice. Flk-sel also induced tubulointerstitial injury, with some tubular epithelial cells expressing α-smooth muscle actin, indicating a phenotypic evolution toward myofibroblasts. In conclusion, prestimulation of VEGFR2 can potentiate subsequent renal injury in mice, an effect enhanced in the setting of nitric oxide deficiency.

Original languageEnglish
Pages (from-to)155-166
Number of pages12
JournalAmerican Journal of Pathology
Issue number1
Publication statusPublished - Jul 2011
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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