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Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions

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Abstract

Diabetic nephropathy, which is associated with loss of human (h) podocytes (PC), is a major complication in diabetes mellitus. High-glucose modulates AMP-activated protein kinase (AMPK) signaling and cell apoptosis. Metformin has been demonstrated to reduce apoptosis and albuminuria in type 2 diabetes. Here, we examined the effect of metformin on cell apoptosis and on pro-/anti-apoptotic signaling in hPC. Expression analyses were done by real-time polymerase chain reaction and western blotting. Moreover, a functional apoptosis assay was performed in hPC. Determination of kinase activation by phosphorylation was done via immunodetection analyses and digital quantification. We found that hPC express organic cation transporter 1 which is the major uptake transporter of metformin. High-glucose reduced AMPK phosphorylation and induced mammalian target of rapamycin (mTOR) activation in podocytes, which was abolished and reversed by pre-treatment with metformin. Furthermore, metformin reduced high-glucose-induced podocytes apoptosis in a concentration-dependent manner. In summary, metformin exhibits an anti-apoptotic impact on podocytes under high-glucose conditions via activation of AMPK and inhibition of mTOR signaling. These data support a beneficial effect of metformin in diabetic nephropathy.

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Authors and Affiliations

  1. Klinische Pharmakologie und Toxikologie, CC04, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

    Sebastian Langer, Reinhold Kreutz & Andreas Eisenreich

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  1. Sebastian Langer
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  2. Reinhold Kreutz
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  3. Andreas Eisenreich
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Correspondence to Andreas Eisenreich.

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None of the authors has any potential conflicts of interest associated with this research. This article does not contain any studies with human participants or animals performed by any of the authors.

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All procedures used in this study are in accordance with institutional and international ethical standards.

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Langer, S., Kreutz, R. & Eisenreich, A. Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions. J Nephrol 29, 765–773 (2016). https://doi.org/10.1007/s40620-015-0258-1

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  • DOI: https://doi.org/10.1007/s40620-015-0258-1

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