Metformin reduces TRPC6 expression through AMPK activation and modulates cytoskeleton dynamics in podocytes under diabetic conditions

Maria Szrejder , Patrycja Rachubik , Dorota Rogacka , Irena Audzeyenka , Michał Rychłowski , Ewelina Kreft , Stefan Angielski , Agnieszka Piwkowska

Abstract

Podocytes have foot processes that comprise an important cellular layer of the glomerular barrier involved in regulating glomerular permeability. The disturbance of podocyte function plays a central role in the development of proteinuria in diabetic nephropathy. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes, and these channels are involved in disturbing the glomerular filtration barrier in diabetes. Metformin is an anti-diabetic drug widely used for treating patients with type 2 diabetes. Recent studies have suggested that the therapeutic effect of metformin might be mediated by AMPK. The precise function of metformin on cellular function and intracellular signaling in podocytes under diabetic conditions is not fully understood. In this study, we demonstrated that metformin normalized TRPC6 expression via AMPKα1 activation in podocytes exposed to high glucose concentrations. A quantitative analysis showed that metformin increased the colocalization of TRPC6 and AMPKα1 subunits from 42% to 61% in standard glucose (SG) medium and from 29% to 52% in high glucose (HG) medium. AMPK activation was also necessary for maintaining appropriate levels of Rho-family small GTPase activity in HG conditions. Moreover, metformin through AMPK activation remodeled cytoskeleton dynamics, and consequently, reduced filtration barrier permeability in diabetic conditions.
Author Maria Szrejder
Maria Szrejder,,
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, Patrycja Rachubik
Patrycja Rachubik,,
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, Dorota Rogacka (FCh / DMBt) - [Polish Academy of Science]
Dorota Rogacka,,
- Department of Molecular Biotechnology
- Polska Akademia Nauk
, Irena Audzeyenka (FCh / DMBt) - [Polish Academy of Science]
Irena Audzeyenka,,
- Department of Molecular Biotechnology
- Polska Akademia Nauk
, Michał Rychłowski (IFB / IB / LVMB)
Michał Rychłowski,,
- Laboratory of Virus Molecular Biology
, Ewelina Kreft
Ewelina Kreft,,
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, Stefan Angielski
Stefan Angielski,,
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, Agnieszka Piwkowska (FCh / DMBt) - [Polish Academy of Science]
Agnieszka Piwkowska,,
- Department of Molecular Biotechnology
- Polska Akademia Nauk
Journal seriesBiochimica et Biophysica Acta-Molecular Basis of Disease, [Biochimica et Biophysica Acta - Molecular Basis of Disease], ISSN 0925-4439, (N/A 140 pkt)
Issue year2020
Vol1866
No3
Pages1-17
Publication size in sheets0.8
Article number165610
Keywords in EnglishFiltration barrier permeability, hyperglycemia, metformin, nephrin, podocytes, TRPC6 channel
ASJC Classification1312 Molecular Biology; 1313 Molecular Medicine
DOIDOI:10.1016/j.bbadis.2019.165610
URL https://doi.org/10.1016/j.bbadis.2019.165610
Languageen angielski
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 09-03-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.181; WoS Impact Factor: 2018 = 4.328 (2) - 2018=5.54 (5)
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