Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury
- 1 October 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 21 (10), 1702-1712
- https://doi.org/10.1681/asn.2010030238
Abstract
Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO-1−/− PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild-type and HO-1–deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1–deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrsate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI.Keywords
This publication has 51 references indexed in Scilit:
- Regulation of autophagy in human and murine cartilage: Hypoxia‐inducible factor 2 suppresses chondrocyte autophagyArthritis & Rheumatism, 2009
- The permissive role of mitochondria in the induction of haem oxygenase-1 in endothelial cellsBiochemical Journal, 2009
- Autophagy is upregulated in rats with status epilepticus and partly inhibited by Vitamin EBiochemical and Biophysical Research Communications, 2009
- Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the ratJournal of Biomedical Science, 2009
- Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal FibrosisJournal of the American Society of Nephrology, 2008
- Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to HypoxiaJournal of Biological Chemistry, 2008
- Autophagy fights disease through cellular self-digestionNature, 2008
- Autophagosome formation: core machinery and adaptationsNature, 2007
- Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4The EMBO Journal, 2007
- LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processingThe EMBO Journal, 2000