Ischemia/reperfusion induce renal tubule apoptosis by inositol 1,4,5-trisphosphate receptor and L-type Ca2+ channel opening.
Recent studies suggest that besides the L-type calcium channel, two calcium channels on the endoplasmic reticulum (ER), the inositol 1,4,5-trisphosphate receptor (InsP3R) and ryanodine receptor (RyR), may play a role in the apoptotic process of renal tubular cells induced by ischemia/reperfusion (I/R) injury. We used antimycin A to induce cell I/R injury in vitro and found an elevation of the cytosolic calcium concentration and consequently apoptosis. Blocking either the L-type calcium channel with nicardipine or the InsP3R with TMB-8 can inhibit cytochrome c release, activate caspase 3 and decrease the apoptotic cell number. However, blocking the RyR with dantrolene had no effect. We further found that Ca(2+) influx through the L-type channel is needed for the opening of the InsP3R which activates a cascade of Ca(2+) release from the ER store. To test these blockers in vivo, in a rat renal I/R model, pretreatment with nicardipine and TMB-8, but not dantrolene, can protect renal function. Taken together, our results suggest that after I/R injury, Ca(2+) influx through the L-type calcium channel triggers the Ca(2+) release from the InsP3R and finally induces apoptosis. The InsP3R could be a new target for the treatment of renal I/R injury.
Wu
Di
D
Department of Nephrology, Kidney Center and Key Laboratory of PLA, General Hospital of PLA, Beijing, PR China.
Chen
Xiangmei
X
Ding
Rui
R
Qiao
Xi
X
Shi
Suozhu
S
Xie
Yuansheng
Y
Hong
Quan
Q
Feng
Zhe
Z
D000818:Animals; D000968:Antimycin A; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D003620:Dantrolene; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009125:Muscle Relaxants, Central; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D019459:Urothelium / Q000378:metabolism
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009125:Muscle Relaxants, Central; D019837:Ryanodine Receptor Calcium Release Channel; D008315:Malondialdehyde; D000968:Antimycin A; D045304:Cytochromes c; D013482:Superoxide Dismutase; D003620:Dantrolene; D002118:Calcium