HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/F410    most recent 00440.2004v1 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 HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Brooks, C. Articles by Dong, Z. Search for Related Content PubMed PubMed Citation Articles by Brooks, C. Articles by Dong, Z.

Acidic pH inhibits ATP depletion-induced tubular cell apoptosis by blocking caspase-9 activation in apoptosome

¹Department of Cellular Biology and Anatomy, ²Center for Genomic Medicine, Medical College of Georgia, Augusta, Georgia; ³Kresge Eye Institute, Wayne State University, Detroit, Michigan; and ⁴Medical Research Service, Department of Veterans Affairs Medical Center, Augusta, Georgia

Submitted 9 December 2004 ; accepted in final form 28 February 2005

Tubular cell apoptosis has been implicated in the development of ischemic renal failure. In in vitro models, ATP depletion-induced apoptosis of tubular cells is mediated by the intrinsic pathway involving Bax translocation, cytochrome c release, and caspase activation. While the apoptotic cascade has been delineated, much less is known about its regulation. The current study has examined the regulation of ATP depletion-induced tubular cell apoptosis by acidic pH, a common feature of tissue ischemia. Cultured renal tubular cells were subjected to 3 h of ATP depletion with azide and then recovered in full culture medium. The treatment led to apoptosis in 40% of cells. Apoptosis was significantly reduced, if the pH of ATP depletion buffer was lowered from 7–7.4 to 6–6.5. This was accompanied by the inhibition of caspase activation. However, acidic pH did not prevent Bax translocation and oligomerization in mitochondria. Cytochrome c release from mitochondria was not blocked either, suggesting that acidic pH inhibited apoptosis at the postmitochondrial level. To determine the postmitochondrial events that were blocked by acidic pH, we conducted in vitro reconstitution experiments. Exogenous cytochrome c, when added into isolated cell cytosol, induced caspase activation. Such activation was abrogated, when pH during the reconstitution was lowered to 6 or 6.5. Nevertheless, acidic pH did not prevent the recruitment and association of caspase-9 by Apaf-1, as shown by coimmunoprecipitation. Together, this study demonstrated the inhibition of tubular cell apoptosis following ATP depletion by acidic pH. A critical step blocked by acidic pH seems to be caspase-9 activation in apoptosome.

ATP depletion; ischemia

This article has been cited by other articles:

				G. Kroemer, L. Galluzzi, and C. Brenner Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev, January 1, 2007; 87(1): 99 - 163. [Abstract] [Full Text] [PDF]

				C. Brooks, J. Wang, T. Yang, and Z. Dong Characterization of cell clones isolated from hypoxia-selected renal proximal tubular cells Am J Physiol Renal Physiol, January 1, 2007; 292(1): F243 - F252. [Abstract] [Full Text] [PDF]

				J. Wang, M. P. Biju, M.-H. Wang, V. H. Haase, and Z. Dong Cytoprotective Effects of Hypoxia against Cisplatin-Induced Tubular Cell Apoptosis: Involvement of Mitochondrial Inhibition and p53 Suppression J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1875 - 1885. [Abstract] [Full Text] [PDF]