Involvement of the AMPK–PTEN pathway in insulin resistance induced by high glucose in cultured rat podocytes

Rogacka, Dorota; Piwkowska, Agnieszka; Audzeyenka, Irena; Angielski, Stefan; Jankowski, Maciej

doi:10.1016/j.biocel.2014.04.008

Cited by 47 publications

(39 citation statements)

References 41 publications

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“…We then targeted PTEN, a lipid phosphatase that dephosphorylates PtdIns-3,4,5-P3 in vivo and is a negative modulator of insulin signaling downstream of the IR/IRS complex [44][45][46]. Recently, it has been shown that the impairment of insulin induction of glucose uptake into podocytes cultured in the presence of high glucose concentrations for long time-periods is associated with increased PTEN levels [32]. We found that Irs2 deficiency increased PTEN levels which elicited a negative regulation of AKT by dephosphorylating the Ser 473 residue as described [47].…”

Section: Discussionmentioning

confidence: 99%

“…We targeted two well-known negative cellular regulators of insulin signaling; protein tyrosine phosphatase 1B (PTP1B) which has been shown to inhibit insulin signaling at the level of IR and is expressed in podocytes [31], and PTEN that regulates AKT activity in the PI3K pathway [32]. No differences were found in PTP1B mRNA (data not shown) or protein expression levels between mPodIRS2KO and mPodWT podocytes (Fig.…”

Section: Knockdown Of Pten But Not Ptp1b Rescues Insulin Sensitivitmentioning

confidence: 95%

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IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Santamaría¹,

Márquez²,

Lay³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2(-/-)). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2(-/-) podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2(-/-) podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

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Section: Discussionmentioning

confidence: 99%

Section: Knockdown Of Pten But Not Ptp1b Rescues Insulin Sensitivitmentioning

confidence: 95%

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Santamaría¹,

Márquez²,

Lay³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Metformin enhances glucose uptake into cells (27, 32). We show that this occurs by reducing SHIP2 activity, as knockdown and overexpression of SHIP2 decreased the ability of metformin to induce glucose uptake in myotubes.…”

Section: Discussionmentioning

confidence: 99%

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.—Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wähälä, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

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“…AMPK is a major regulator of insulin-dependent glucose uptake and insulin signaling in podocytes [18]. Phosphorylation of AMPK at Thr172 is required for the activation of AMPK [32], and Ca…”

Section: Discussionmentioning

confidence: 99%

“…AMP-activated protein kinase (AMPK) activity appears to positively regulate insulindependent glucose uptake and insulin signaling [16,17]; however, AMPK activity is suppressed in disorders associated with insulin resistance [4,18]. The AMPK is composed of three subunits, one catalytic, termed a, and two regulatory, termed b and g. The activation of AMPK requires the phosphorylation of threonine 172 (Thr172) within the catalytic a subunit by upstream kinases, namely the Ca 2+ /calmodulin-dependent kinase kinase-β (CaMKK-β) and/or the LKB1-STRAD-MO25 complex [19].…”

Section: Introductionmentioning

confidence: 99%

The TRPC6-AMPK Pathway is Involved in Insulin-Dependent Cytoskeleton Reorganization and Glucose Uptake in Cultured Rat Podocytes

Rachubik¹,

Szrejder²,

Rogacka³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Podocytes are dynamic polarized cells on the surface of glomerular capillaries that are an essential part of the glomerular filtration barrier. 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 are involved in regulating glomerular filtration. Here we investigated whether the AMPK-TRPC6 pathway is involved in insulin-dependent cytoskeleton reorganization and glucose uptake in cultured rat podocytes. Methods: Western blot and immunofluorescence analysis confirmed AMPKα and TRPC6 expression, the phosphorylation of proteins associated with actin cytoskeleton reorganization (PAK, rac1, and cofilin), and the expression of insulin signaling proteins (Akt, Insulin receptor). Coimmunoprecipitation and immunofluorescence results demonstrated AMPKα/TRPC6 interaction. To ask whether TRPC6 is involved in the insulin regulation of glucose transport, we measured insulin-dependent (1, 2-³H)-deoxy-D-glucose uptake into podocytes after reducing TRPC6 activity pharmacologically and biochemically (TRPC6 siRNA). Results: The results suggested a key role for the TRPC6 channel in the mediation of insulin-dependent activation of AMPKα2 and glucose uptake. Moreover, AMPK and TRPC6 activation were required to stimulate the Rac1 signaling pathway. Conclusion: These results suggest a potentially important new mechanism that regulates glucose transport in podocytes and that could be injurious during diabetes.

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Involvement of the AMPK–PTEN pathway in insulin resistance induced by high glucose in cultured rat podocytes

Cited by 47 publications

References 41 publications

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

The TRPC6-AMPK Pathway is Involved in Insulin-Dependent Cytoskeleton Reorganization and Glucose Uptake in Cultured Rat Podocytes

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