Cyclosporine stimulates the renal epithelial sodium channel by elevating cholesterol.
Cyclosporine A (CsA) is an efficient immunosuppressant used for reducing allograft rejection but with a severe side effect of causing hypertension. We hypothesize that the renal epithelial sodium channel (ENaC) may participate in CsA-induced hypertension. In the present study, we used the patch-clamp cell-attached configuration to examine whether and how CsA stimulates ENaC in A6 distal nephron cells. The data showed that CsA significantly increased ENaC open probability. Since CsA is an inhibitor of the ATP-binding cassette A1 (ABCA1) transporter, we employed 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), another ABCA1 inhibitor, and found that DIDS mimicked the effects of CsA on ENaC basal and cholesterol-induced activity but without any additive effect if combined with CsA. CsA and DIDS also had an identical effect on reduced ENaC activity caused by cholesterol extraction. ABCA1 protein was detected in A6 cells by Western blot analysis. Confocal microscopy data showed that both CsA and DIDS facilitated A6 cells to uptake cholesterol. Since enhanced ENaC activity is known to cause hypertension, these data together suggest that CsA may cause hypertension by stimulating ENaC through a pathway associated with inhibition of ABCA1 and consequent elevation of cholesterol in the cells.
Wang
Jing
J
Division of Nephrology, Univ. of Alabama at Birmingham, 1530 Third Ave. South, Zeigler Research Bldg. 510, Birmingham, AL 35294, USA.
Zhang
Zhi-Ren
ZR
Chou
Chu-Fang
CF
Liang
You-You
YY
Gu
Yuchun
Y
Ma
He-Ping
HP
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D014982:Xenopus laevis; D047392:beta-Cyclodextrins / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D007166:Immunosuppressive Agents; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D016572:Cyclosporine; D002784:Cholesterol; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid