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This Article Full Text Full Text (PDF) All Versions of this Article: 293/2/F533    most recent 00030.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Caplanusi, A. Articles by Navar, L. G. Search for Related Content PubMed PubMed Citation Articles by Caplanusi, A. Articles by Navar, L. G.

Metabolic inhibition-induced transient Ca²⁺ increase depends on mitochondria in a human proximal renal cell line

¹Department of Physiology and Hypertension and Renal Center of Excellence and ²Nephrology Section, Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans; ³Department of Medical Biochemistry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; and ⁴Southeast Louisiana Veterans Healthcare System, New Orleans, Louisiana

Submitted 16 January 2007 ; accepted in final form 19 May 2007

During ischemia or hypoxia an increase in intracellular cytosolic Ca²⁺ induces deleterious events but is also implicated in signaling processes triggered in such conditions. In MDCK cells (distal tubular origin), it was shown that mitochondria confer protection during metabolic inhibition (MI), by buffering the Ca²⁺ overload via mitochondrial Na⁺-Ca²⁺ exchanger (NCX). To further assess this process in cells of human origin, human cortical renal epithelial cells (proximal tubular origin) were subjected to MI and changes in cytosolic Ca²⁺ ([Ca²⁺]_i), Na⁺, and ATP concentrations were monitored. MI was accomplished with both antimycin A and 2-deoxyglucose and induced a 3.5-fold increase in [Ca²⁺]_i, reaching 136.5 ± 15.8 nM in the first 3.45 min. Subsequently [Ca²⁺]_i dropped and stabilized to 62.7 ± 7.3 nM by 30 min. The first phase of the transient increase was La³⁺ sensitive, not influenced by diltiazem, and abolished when mitochondria were deenergized with the protonophore carbonylcyanide p-trifluoromethoxyphenylhydrazone. The subsequent recovery phase was impaired in a Na⁺-free medium and weakened when the mitochondrial NCX was blocked with 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157). Thus Ca²⁺ entry is likely mediated by store-operated Ca²⁺ channels and depends on energized mitochondria, whereas [Ca²⁺]_i recovery relied partially on the activity of mitochondrial NCX. These results indicate a possible mitochondrial-mediated signaling process triggered by MI, support the hypothesis that mitochondrial NCX has an important role in the Ca²⁺ clearance, and overall suggest that mitochondria play a preponderant role in the regulation of responses to MI in human renal epithelial cells.

Ca²⁺ influx; energized mitochondria; mitochondrial Na⁺-Ca²⁺ exchanger; thapsigargin; CGP-37157