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Ischemia/reperfusion induce renal tubule apoptosis by inositol 1,4,5-trisphosphate receptor and L-type Ca2+ channel opening.

Abstract
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.
AuthorsDi Wu, Xiangmei Chen, Rui Ding, Xi Qiao, Suozhu Shi, Yuansheng Xie, Quan Hong, Zhe Feng
JournalAmerican journal of nephrology (Am J Nephrol) Vol. 28 Issue 3 Pg. 487-99 ( 2008) ISSN: 1421-9670 [Electronic] Switzerland
PMID18185015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright(c) 2008 S. Karger AG, Basel.
Chemical References
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Inositol 1,4,5-Trisphosphate Receptors
  • Muscle Relaxants, Central
  • Ryanodine Receptor Calcium Release Channel
  • Malondialdehyde
  • Antimycin A
  • Cytochromes c
  • Superoxide Dismutase
  • Dantrolene
  • Calcium
Topics
  • Animals
  • Antimycin A
  • Apoptosis (drug effects)
  • Blood Pressure (drug effects)
  • Calcium (metabolism)
  • Calcium Channel Blockers
  • Calcium Channels, L-Type (metabolism)
  • Cells, Cultured
  • Cytochromes c (metabolism)
  • DNA Fragmentation (drug effects)
  • Dantrolene
  • Endoplasmic Reticulum (metabolism)
  • Epithelial Cells (metabolism)
  • Inositol 1,4,5-Trisphosphate Receptors (antagonists & inhibitors, metabolism)
  • Kidney Tubules, Proximal (metabolism, pathology)
  • Male
  • Malondialdehyde (metabolism)
  • Muscle Relaxants, Central
  • Rats
  • Rats, Wistar
  • Reperfusion Injury (enzymology, metabolism, pathology)
  • Ryanodine Receptor Calcium Release Channel (metabolism)
  • Superoxide Dismutase (metabolism)
  • Urothelium (metabolism)

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