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

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

doi:10.1016/j.bbadis.2019.165610

Cited by 43 publications

(30 citation statements)

References 49 publications

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“…Our research group previously found that HG conditions increase albumin permeability in rat glomeruli and cultured rat podocytes, accompanied by F-actin redistribution to cortical regions of podocytes [47][48][49]. However, to our knowledge, the present study is the first report of an analogous effect of hyperglycemia on human podocytes.…”

Section: Discussioncontrasting

confidence: 40%

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Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Typiak

Kulesza

Rachubik

et al. 2021

IJMS

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Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.

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Section: Discussioncontrasting

confidence: 40%

“…Human podocytes and rat glomerulus lysates were prepared, as described previously [49,52]. Amicon Ultra Centrifugal Filters (catalog no.…”

Section: Western Blotmentioning

confidence: 99%

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Typiak

Kulesza

Rachubik

et al. 2021

IJMS

Self Cite

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“…The authors reported also a 5-fold increase in AMPK phosphorylation associated with an increase in the histone deacetylase (HDAC) activity in mouse spermatozoa [24]. Moreover, several recent studies have shown that metformin through AMPK activation remodeled cytoskeleton dynamics [56]. We can hypothesize that metformin/AMPK phosphorylated protein associated with the microtubules in flagella such as A kinase-anchoring protein (AKAP), a PKA substrate implicated in a flagellar beating.…”

Section: Discussionmentioning

confidence: 99%

Metformin Improves Quality of Post-Thaw Canine Semen

Grandhaye

Partyka

Ligocka

et al. 2020

Animals

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Sperm cryopreservation is an assisted reproductive technique routinely used in canine species for genetic conservation. However, during cryopreservation, the DNA damages are still elevated, limiting the fertilization rate. The present study was conducted to evaluate whether supplementation of canine semen extender with a molecule limiting the metabolic activities can improve the quality of frozen-thawed canine spermatozoa. We used metformin, known to limit the mitochondrial respiratory and limit the oxidative stress. Before and during the freezing procedure, metformin (50µM and 500µM) has been added to the extender. After thawing, sperm exposed to metformin conserved the same viability without alteration in the membrane integrity or acrosome reaction. Interestingly, 50µM metformin improved the sperm motility in comparison to the control, subsequently increasing mitochondrial activity and NAD+ content. In addition, the oxidative stress level was reduced in sperm treated with metformin improving the sperm quality as measured by a different molecular marker. In conclusion, we have shown that metformin is able to improve the quality of frozen-thawed dog semen when it is used during the cryopreservative procedure.

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“…4A, Figure S4). Metformin has been shown to promote mitochondrial metabolism via regulation of redox state (33)(34)(35)(36)(37), activation of AMPK (38)(39)(40)(41)(42) and increased the production of lactate (43)(44)(45)(46). Here, metformin was unable to restore intra-tissue lactate or TCA metabolite levels in iMSUD mice unlike in wild type mice, suggesting that BCKDH function is required for metformin action (Fig.…”

Section: Global Dysfunction In Oxidative Carbon Metabolism Caused By mentioning

confidence: 92%

Metformin extends the lifespan of iMSUD mice by rescuing physiologic dysfunction and modulating mechanisms of mTORC1 activation

Hsu

Davis

Liao

et al. 2020

Preprint

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Abstract Background- Dysregulation of branched chain amino acid (BCAA) catabolism caused by mutations in the metabolizing enzyme-branched chain alpha-keto acid dehydrogenase (BCKDH) leads to the fatal newborn disorder Maple Syrup Urine Disease (MSUD) and is linked to chronic diseases such as type 2 diabetes. Results- Here we show that a MSUD mouse model with severely reduced BCKDH activity exhibits glucose intolerance, altered mTOR signaling, decreased levels of TCA cycle intermediates, reduced distribution of Type I skeletal muscle fibers and activated AMP-activated protein kinase (AMPK) signaling, all of which can be ameliorated by long term treatment with metformin, which enhances the survival of these mice. Treatment with metformin was correlated with increased serum-levels of growth/differentiation factor GDF15 (GFD15) and adiponectin. We also found that branched chain keto acid regulates leucine-mediated activation of mTORC1 by preventing the dissociation of sestrin2-gator complex in vitro. Conclusions- In summary, our study suggests metformin could be an effective therapeutic candidate for MSUD patients and maps the crosstalk between key pathways that maintain metabolic homeostasis in MSUD.

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

Cited by 43 publications

References 49 publications

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Metformin Improves Quality of Post-Thaw Canine Semen

Metformin extends the lifespan of iMSUD mice by rescuing physiologic dysfunction and modulating mechanisms of mTORC1 activation

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