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J Nephrol. 2016 Dec;29(6):765-773. Epub 2016 Jan 5.

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

Author information

1
Klinische Pharmakologie und Toxikologie, CC04, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
2
Klinische Pharmakologie und Toxikologie, CC04, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. andreas.eisenreich@charite.de.

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.

KEYWORDS:

Apoptosis; Diabetic nephropathy; Glucose; Podocytes

PMID:
26733332
DOI:
10.1007/s40620-015-0258-1
[Indexed for MEDLINE]

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