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

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 mmol/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.

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

“…Although H 2 S is very toxic at high concentrations, it is produced at low concentrations by the degradation of cysteine or homocysteine by CGL or CBS, and acts in the vasculature and the brain as a signaling molecule, reducing blood pressure (Yang et al., 2008), and preventing neurodegeneration (Paul & Snyder, 2012). Furthermore, exogenous H 2 S can also extend the lifespan of worms (Miller & Roth, 2007) and prevent kidney injury in some experimental models (Bos et al., 2009; Holwerda et al., 2014). Thus, it is apparent that H 2 S has a protective role in tissues in a number of species.…”

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…Additionally, H 2 S is not beneficial in all models of renal injury as its effect can vary with the context (70). Whereas H 2 S ameliorates renin-induced hypertension (71), ischemia-reperfusion injury in the kidney and heart (17,20), obstructive kidney injury (72), preeclampsia (73), and hyperhomocysteinemia-induced chronic kidney disease (74) and protects endothelium against high glucose (75), it assumes a pathologic role as a mediator in cisplatinum-induced kidney cell injury (76), streptozotocin-induced pancreatic ␤ cell injury (77), and colon carcinoma (78). These considerations suggest that a critical evaluation of PDE5 inhibitors and H 2 S donors should be done in long term models of kidney injury in diabetes.…”

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines

“…Gene expression of VEGF in the kidneys was also increased, suggesting that the proangiogenic effects of H 2 S are mediated by VEGF. Clinically, the rats showed decreased proteinuria, hypertension, and glomerular injury (38). Conversely, decreased levels of the precursor molecules of H 2 S have been found in patients with preeclampsia (37,39,40).…”

“…This mechanism may be dependent on VEGF. When rats that were injected with adenovirus overexpressing sFlt-1 were treated with H 2 S donor sodium hydrosulfide, they showed decreased levels of serum sFlt-1 and increased serum VEGF (38). Gene expression of VEGF in the kidneys was also increased, suggesting that the proangiogenic effects of H 2 S are mediated by VEGF.…”