AUTHOR=Wang Qiu-Shi , Liang Chen , Jiang Shuai , Zhu Di , Sun Yu , Niu Na , Yang Xu , Yang Yan-Chao , Dong Bi-Han , Yao Jie , Yu Chang-Jiang , Lou Jie , Tang Liang-Liang , Wu Ming-Ming , Zhang Zhi-Ren , Ma He-Ping 

TITLE=NaHS or Lovastatin Attenuates Cyclosporine A–Induced Hypertension in Rats by Inhibiting Epithelial Sodium Channels

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.665111

DOI=10.3389/fphar.2021.665111

ISSN=1663-9812

ABSTRACT=Use of cyclosporine A (CsA) in transplant recipients is limited due to its side effects of causing severe hypertension. We have previously shown that CsA stimulates the epithelial sodium channel (ENaC) in cultured distal nephron cells. However, it remains unknown whether ENaC mediates CsA-induced hypertension and how we could prevent the hypertension. Our data show that the open probability (PO) of ENaC in principal cells of split-open cortical collecting ducts was significantly increased after treatment of rats with CsA; the increase was attenuated by lovastatin. Moreover, CsA also elevated the levels of intracellular cholesterol, intracellular ROS via activation of NADPH oxidase p47phox, serum- and glucocorticoid-induced kinase isoform 1 (Sgk1), and phosphorylated neural precursor cell-expressed developmentally down-regulated protein 4-2 (p-Nedd4-2) in the kidney cortex. Lovastatin also abolished CsA-induced elevation of α, β and γ-ENaC expression. CsA elevated SBP in rats; the elevation was completely reversed by lovastatin (an inhibitor of cholesterol synthesis), NaHS (a donor of H2S) which NaHS ameliorated CsA-induced elevation of ROS level, or amiloride (a potent ENaC blocker). These results suggest that CsA induces hypertension by stimulating ENaC via a signaling cascade associated with elevation of intracellular ROS, activation of Sgk1, and inactivation of Nedd4-2 in an intracellular cholesterol-dependent manner. Our date also show that NaHS ameliorates CsA-induced hypertension by inhibition of oxidative stress.