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Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression

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Abstract

The goal of the study is to examine the relationship between the sensor molecules, Hypoxia Inducible Factor-1 (HIF-1), AMP activated Protein Kinase (AMPK) and mammalian Target of Rapamycin (mTOR) in chondrocyte survival and autophagy. We showed that chondrocytes expressed the energy sensor AMPK-1 and that activation increased with maturation. In addition, we showed that thapsigargin treatment activated AMPK and autophagy in a HIF-1-dependent manner. Using serum-starved AMPK-silenced cells, we demonstrated that AMPK was required for the induction of the autophagic response. We also noted a change in chondrocyte sensitivity to apoptogens, due to activation of caspase-8 and cleavage and activation of the pro-apoptotic protein, BID. To test the hypothesis that AMPK signaling directly promoted autophagy, we inhibited AMPK activity in mTOR silenced cells and showed that while mTOR suppression induced autophagy, AMPK inhibition did not block this activity. Based on these findings, it is concluded that because of the micro-environmental changes experienced by the chondrocyte, autophagy is activated by AMPK in a HIF-1-dependent manner.

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Acknowledgements

This work was supported by NIH grants DE 015694 and DE 016383 (to VS) and DE 010875 and DE 013319 (to IMS).

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Correspondence to Vickram Srinivas or Irving M. Shapiro.

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Bohensky, J., Leshinsky, S., Srinivas, V. et al. Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression. Pediatr Nephrol 25, 633–642 (2010). https://doi.org/10.1007/s00467-009-1310-y

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  • DOI: https://doi.org/10.1007/s00467-009-1310-y

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