TY - JOUR
T1 - Attenuation of indoxyl sulfate–induced cell damage by cinchonidine—a Cinchona alkaloid—through the downregulation of p53 signaling pathway by promoting MDM2 cytoplasmic-nuclear shuttling in endothelial cells
AU - Teng, Ruei Dun
AU - Yang, Chih Hao
AU - Chung, Chi Li
AU - Sheu, Joen Rong
AU - Hsieh, Cheng Ying
N1 - Funding Information:
This work was supported by grants provided by the Ministry of Science and Technology of Taiwan ( MOST109-2314-B-038-095-MY3 , MOST110-2320-B-038-063 ) and the Taipei Medical University ( DP2-111-21121-01-N-08-02 ).
Funding Information:
This work was supported by grants provided by: the Ministry of Science and Technology of Taiwan ( MOST109-23 14-B-038-095-MY3 , MOST110-2320-B-038-063 ) and the Taipei Medical University ( DP2-111-21121-01-N-08-02 ).
Publisher Copyright:
© 2023
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Renocardiac syndromes are a critical concern among patients with chronic kidney disease (CKD). High level of indoxyl sulfate (IS), a protein-bound uremic toxin, in plasma is known to promote the pathogenesis of cardiovascular diseases by impairing endothelial function. However, the therapeutic effects of the adsorbent of indole, a precursor of IS, on renocardiac syndromes is still debated. Therefore, novel therapeutic approaches should be developed to treat IS-associated endothelial dysfunction. In the present study, we have found that cinchonidine, a major Cinchona alkaloid, exhibited superior cell-protective effects among the 131 test compounds in IS-stimulated human umbilical vein endothelial cells (HUVECs). IS-induced cell death, cellular senescence, and impairment of tube formation in HUVECs were substantially reversed after treatment with cinchonidine. Despite the cinchonidine did not alter reactive oxygen species formation, cellular uptake of IS and OAT3 activity, RNA-Seq analysis showed that the cinchonidine treatment downregulated p53-modulated gene expression and substantially reversed IS-caused G0/G1 cell cycle arrest. Although the mRNA levels of p53 were not considerably downregulated by cinchonidine in IS-treated HUVECs, the treatment of cinchonidine promoted the degradation of p53 and the cytoplasmic-nuclear shuttling of MDM2. Cinchonidine exhibited cell-protective effects against the IS-induced cell death, cellular senescence, and impairment of vasculogenic activity in HUVECs through the downregulation of p53 signaling pathway. Collectively, cinchonidine may be a potential cell-protective agent to rescue IS-induced endothelial cell damage.
AB - Renocardiac syndromes are a critical concern among patients with chronic kidney disease (CKD). High level of indoxyl sulfate (IS), a protein-bound uremic toxin, in plasma is known to promote the pathogenesis of cardiovascular diseases by impairing endothelial function. However, the therapeutic effects of the adsorbent of indole, a precursor of IS, on renocardiac syndromes is still debated. Therefore, novel therapeutic approaches should be developed to treat IS-associated endothelial dysfunction. In the present study, we have found that cinchonidine, a major Cinchona alkaloid, exhibited superior cell-protective effects among the 131 test compounds in IS-stimulated human umbilical vein endothelial cells (HUVECs). IS-induced cell death, cellular senescence, and impairment of tube formation in HUVECs were substantially reversed after treatment with cinchonidine. Despite the cinchonidine did not alter reactive oxygen species formation, cellular uptake of IS and OAT3 activity, RNA-Seq analysis showed that the cinchonidine treatment downregulated p53-modulated gene expression and substantially reversed IS-caused G0/G1 cell cycle arrest. Although the mRNA levels of p53 were not considerably downregulated by cinchonidine in IS-treated HUVECs, the treatment of cinchonidine promoted the degradation of p53 and the cytoplasmic-nuclear shuttling of MDM2. Cinchonidine exhibited cell-protective effects against the IS-induced cell death, cellular senescence, and impairment of vasculogenic activity in HUVECs through the downregulation of p53 signaling pathway. Collectively, cinchonidine may be a potential cell-protective agent to rescue IS-induced endothelial cell damage.
KW - Cinchonidine
KW - Endothelial dysfunction
KW - Indoxyl sulfate
KW - MDM2
KW - p53
KW - Renocardiac syndromes
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U2 - 10.1016/j.lfs.2023.121477
DO - 10.1016/j.lfs.2023.121477
M3 - Article
C2 - 36796718
AN - SCOPUS:85148749423
SN - 0024-3205
VL - 318
JO - Life Sciences
JF - Life Sciences
M1 - 121477
ER -