Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

Kim M. Holwerda, Suzanne D. Burke, Marijke M. Faas, Zsuzsanna Zsengeller, Isaac E. Stillman, Peter M. Kang, Harry van Goor, Amy McCurley, Iris Z. Jaffe, S. Ananth Karumanchi, A. Titia Lely*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

75 Citations (Scopus)

Abstract

Soluble fms-like tyrosine kinase 1 (sFlt1), a circulating antiangiogenic protein, is elevated in kidney diseases and contributes to the development of preeclampsia. Hydrogen sulfide is a vasorelaxant and proangiogenic gas with therapeutic potential in several diseases. Therefore, we evaluated the potential therapeutic effect and mechanisms of action of hydrogen sulfide in an animal model of sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis created by adenovirus-mediated overexpression of sFlt1 in Sprague-Dawley rats. We injected sFlt1-overexpressing animals intraperitoneally with the hydrogen sulfide-donor sodium hydrosulfide (NaHS) (50 mu mol/kg, twice daily) or vehicle (n=7 per group). Treatment with NaHS for 8 days significantly reduced sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis. Measurement of plasma protein concentrations with ELISA revealed a reduction of free plasma sFlt1 and an increase of free plasma vascular endothelial growth factor (VEGF) after treatment with NaHS. Renal VEGF-A mRNA expression increased significantly with NaHS treatment. In vitro, NaHS was proangiogenic in an endothelial tube assay and attenuated the antiangiogenic effects of sFlt1. Stimulation of podocytes with NaHS resulted in both short-term VEGF release (120 minutes) and upregulation of VEGF-A mRNA levels (24 hours). Furthermore, pretreatment of mesenteric vessels with a VEGF receptor 2-neutralizing antibody significantly attenuated NaHS-induced vasodilation. These results suggest that hydrogen sulfide ameliorates sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis in rats by increasing VEGF expression. Further studies are warranted to evaluate the role of hydrogen sulfide as a novel therapeutic agent for vascular disorders such as preeclampsia.

Original languageEnglish
Pages (from-to)717-725
Number of pages9
JournalJournal of the American Society of Nephrology
Volume25
Issue number4
DOIs
Publication statusPublished - Apr-2014

Keywords

  • CYSTATHIONINE GAMMA-LYASE
  • ISCHEMIA/REPERFUSION INJURY
  • ANGIOGENIC FACTORS
  • TYROSINE KINASE-1
  • SOLUBLE ENDOGLIN
  • NITRIC-OXIDE
  • RAT MODEL
  • PREECLAMPSIA
  • VEGF
  • RECEPTOR

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