TY - JOUR
T1 - Hydralazine improves ischemia-induced neovasculogenesis via xanthine-oxidase inhibition in chronic renal insufficiency
AU - Chang, Ting Ting
AU - Chen, Jaw Wen
N1 - Funding Information:
This study was partially supported by the project MOST-104-2811-B-010-038 , MOST-105-2811-B-010-023 , and MOST-106-2811-B-010-026 (to Jaw-Wen Chen) from the Ministry of Science and Technology, Executive Yuan, Taiwan, R.O.C. , and by the project V104C-101 (to Jaw-Wen Chen) from Taipei Veterans General Hospital, Taipei, Taiwan R.O.C. . Appendix A
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2020/1
Y1 - 2020/1
N2 - Oxidative stress is related to the progression of renal diseases and modulation of oxidative stress can lead to a reduction in vascular events in patients with chronic renal insufficiency (CRI). Indoxyl sulfate (IS) and xanthine oxidase (XO) are related to impaired neovasculogenesis in CRI. Hydralazine is suggested for blood pressure control in CRI. This study aimed to investigate whether hydralazine could improve ischemia-induced neovasculogenesis in CRI animals by reducing reactive oxygen species (ROS) levels. Mice underwent subtotal nephrectomy or sham surgery. Nitrendipine, probenecid, and allopurinol were used to reduce blood pressure, uric acid (UA), and XO activity levels, respectively, for comparison. Blood pressure, XO activity and UA levels that were increased after subtotal nephrectomy were reduced by hydralazine treatment. Allopurinol decreased blood XO activity and UA levels. Only hydralazine and allopurinol increased the number of circulating endothelial progenitor cells (EPCs) and improved neovasculogenesis in CRI mice. IS activated XO mRNA and ROS and inhibited the functions of EPCs and endothelial cells, which could be reversed by hydralazine. However, no additional beneficial effects were observed when XO was inhibited with both hydralazine and siRNA. In conclusion, hydralazine, as a potential XO inhibitor, not only reduced blood pressure and UA levels but also increased the number of circulating EPCs and improved neovasculogenesis in CRI animals. Hydralazine directly inhibited IS-induced ROS and XO activation in EPCs and endothelial cells, and restored their functions in vitro. Future studies should evaluate whether hydralazine could provide additional vascular protection in patients with CRI.
AB - Oxidative stress is related to the progression of renal diseases and modulation of oxidative stress can lead to a reduction in vascular events in patients with chronic renal insufficiency (CRI). Indoxyl sulfate (IS) and xanthine oxidase (XO) are related to impaired neovasculogenesis in CRI. Hydralazine is suggested for blood pressure control in CRI. This study aimed to investigate whether hydralazine could improve ischemia-induced neovasculogenesis in CRI animals by reducing reactive oxygen species (ROS) levels. Mice underwent subtotal nephrectomy or sham surgery. Nitrendipine, probenecid, and allopurinol were used to reduce blood pressure, uric acid (UA), and XO activity levels, respectively, for comparison. Blood pressure, XO activity and UA levels that were increased after subtotal nephrectomy were reduced by hydralazine treatment. Allopurinol decreased blood XO activity and UA levels. Only hydralazine and allopurinol increased the number of circulating endothelial progenitor cells (EPCs) and improved neovasculogenesis in CRI mice. IS activated XO mRNA and ROS and inhibited the functions of EPCs and endothelial cells, which could be reversed by hydralazine. However, no additional beneficial effects were observed when XO was inhibited with both hydralazine and siRNA. In conclusion, hydralazine, as a potential XO inhibitor, not only reduced blood pressure and UA levels but also increased the number of circulating EPCs and improved neovasculogenesis in CRI animals. Hydralazine directly inhibited IS-induced ROS and XO activation in EPCs and endothelial cells, and restored their functions in vitro. Future studies should evaluate whether hydralazine could provide additional vascular protection in patients with CRI.
KW - Chronic renal insufficiency
KW - Endothelial progenitor cells
KW - Hydralazine
KW - Neovasculogenesis
KW - Uric acid
KW - Xanthine oxidase
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U2 - 10.1016/j.phrs.2019.104509
DO - 10.1016/j.phrs.2019.104509
M3 - Article
C2 - 31678640
AN - SCOPUS:85075306059
SN - 1043-6618
VL - 151
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 104509
ER -