title: Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions.
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.
authors.affiliation: Klinische Pharmakologie und Toxikologie, CC04, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Langer
authors.affiliation: Klinische Pharmakologie und Toxikologie, CC04, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
authors.affiliation: Klinische Pharmakologie und Toxikologie, CC04, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. andreas.eisenreich@charite.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Eisenreich
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D027702:Organic Cation Transporter 1; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: Apoptosis; Diabetic nephropathy; Glucose; Podocytes