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Inhibition of MTOR disrupts autophagic flux in podocytes.

ABSTRACT: Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.

SUBMITTER: Cina DP

PROVIDER: S-EPMC3294311 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Inhibition of MTOR disrupts autophagic flux in podocytes.

Cinà Davide P DP Onay Tuncer T Paltoo Aarti A Li Chengjin C Maezawa Yoshiro Y De Arteaga Javier J Jurisicova Andrea A Quaggin Susan E SE

Journal of the American Society of Nephrology : JASN 20111222 3

Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage ...[more]

PMID: 22193387

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Inhibition of MTOR disrupts autophagic flux in podocytes.

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Inhibition of MTOR disrupts autophagic flux in podocytes.

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