Permolybdate and Pertungstate-Potent Stimulators of Insulin Effects in Rat Adipocytes: Mechanism of Action

Li, Jinping; Elberg, Gerard; Gefel, Dov; Shechter, Yoram

doi:10.1021/bi00018a026

Cited by 77 publications

(81 citation statements)

References 37 publications

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“…The loss of pY during hypoxia was mediated by vanadate-sensitive phosphatases, because it was almost entirely blocked in tubules treated with pervanadate ( Figure 10A, 40,41 ). The pervanadate-treated tubules had better retention of basal staining for pY, but it was still markedly decreased relative to controls ( Figure 10C).…”

Section: Resultsmentioning

confidence: 99%

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Energetic Determinants of Tyrosine Phosphorylation of Focal Adhesion Proteins during Hypoxia/Reoxygenation of Kidney Proximal Tubules

Weinberg¹,

Venkatachalam²,

Roeser³

et al. 2001

The American Journal of Pathology

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Anaerobic mitochondrial metabolism of ␣-ketoglutarate and aspartate or ␣-ketoglutarate and malate can prevent and reverse severe mitochondrial dysfunction during reoxygenation after 60 minutes of hypoxia in kidney proximal tubules. 34 The present studies demonstrate that, during hypoxia, paxillin, focal adhesion kinase, and p130 cas migrated faster by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, their phosphotyrosine (pY) content decreased to ϳ5% of that in oxygenated tubules without changes in total protein, and the normally basal immunostaining of ␤1 and ␣6 integrin subunits, pY, and paxillin was lost or markedly decreased. During reoxygenation without supplemental substrates, recovery of pY and basal localization of the focal adhesion proteins was poor. ␣-Ketoglutarate and aspartate, which maintained slightly higher levels of ATP during hypoxia, also maintained 2.5-fold higher levels of pY during this period, and promoted full recovery of pY content and basal localization of focal adhesion proteins during subsequent reoxygenation. Similarly complete recovery was made possible by provision of ␣-ketoglutarate and aspartate or ␣-ketoglutarate and malate only during reoxygenation. These data emphasize the importance of very low energy thresholds for maintaining the integrity of key structural and biochemical components required for cellular survival and reaffirm the value of approaches aimed at conserving or generating energy in cells injured by hypoxia or ischemia. Ischemic and related forms of acute renal failure result from a complex interplay of vascular and tubular events that can vary in their relative contributions depending on characteristics of the specific clinical situation or experimental model. Although the process is frequently also termed acute tubular necrosis, much of the tubule cell damage in both animal models and human acute renal failure is sublethal and reversible within affected cells. [1][2][3][4][5][6] Effects on multiple subcellular structures have been described including loss of brush border microvilli and simplification of the basolateral membrane, 1-3 disruption of the normal polar distribution of major membrane-associated proteins including Na ϩ ,K ϩ -ATPase and its associated cytoskeletal proteins, 7,8 disruption of tight junctions and adherens junctions, 5,9 -13 and abnormalities of integrin distribution and function, 14 -19 all of which can contribute to impaired barrier function and vectorial transport by the epithelium. ATP depletion and the resulting protein dephosphorylation 10 -13,20,21 are the primary processes initiating these events.Proximal tubules have relatively little or no glycolytic capacity making them dependent on mitochondrial metabolism for ATP synthesis. 22,23 Freshly isolated proximal tubules rapidly develop lethal damage when subjected to hypoxia or other ATP-depleting maneuvers, 24 -27 which has limited their utility for studying reversible structural and metabolic alterations. This situation has improved with recognition that much of their se...

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Section: Resultsmentioning

confidence: 99%

“…Pervanadate was prepared fresh before each use by adding hydrogen peroxide in a 2:1 molar ratio to a 100ϫ stock solution of sodium orthovanadate. 40,41 Addition of catalase to the pervanadate to quench excess hydrogen peroxide did not alter its effects on the tubules.…”

Section: Reagentsmentioning

confidence: 94%

Energetic Determinants of Tyrosine Phosphorylation of Focal Adhesion Proteins during Hypoxia/Reoxygenation of Kidney Proximal Tubules

Weinberg¹,

Venkatachalam²,

Roeser³

et al. 2001

The American Journal of Pathology

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“…Phosphatase (pNPPase) Assay-PTPases hydrolyze pNPP efficiently (4,15,22). pNPPase activity was measured as described (4,22), with some modifications to achieve measurements on cells grown in 96-well plates.…”

Section: )mentioning

confidence: 99%

“…PV and PMo inhibit cytosolic PTPase with IC 50 values of 3.3 and 10 M, respectively, in a cell-free system (15). However, PMo was probably generated in a suboptimal way by Li et al (15).…”

Section: Inhibition Of Phosphatases By Pv and Pmomentioning

confidence: 99%

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Properties of Pervanadate and Permolybdate

Mikalsen¹,

Kaalhus²

1998

Journal of Biological Chemistry

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Pervanadate and permolybdate are irreversible protein-tyrosine phosphatase inhibitors, with IC 50 values of 0.3 and 20 M, respectively, in intact cells. Maximal inhibition was obtained within 1 min at higher concentrations of the compounds. They induced prominent changes in the phosphorylation status of the gap junction protein, connexin43. These effects were utilized as model systems to assess the stability and inactivation of the compounds. Although the concentrated stock solutions were relatively stable, the diluted compounds were unstable. The biological activity had decreased to 20 -30% after 6 h of incubation in a phosphate buffer, 1 h in phosphate buffer with 10% fetal calf serum, and 1-3 minutes in culture medium. Thiols reacted rapidly with the compounds and inactivated them (initial reaction rates with cysteine: permolybdate > pervanadate > H 2 O 2 ). Catalase inactivated the compounds, and permolybdate was the more sensitive. The cells inactivated permolybdate faster than pervanadate. Cellular inactivation of permolybdate, and to a lesser degree pervanadate, appeared to be partly dependent on catalase and thiols. However, a general decrease in cellular thiols was not the mediator of the biological effects of pervanadate or permolybdate. Mathematical modeling of the thiol reactivity suggested that monoperoxovanadate at maximum could possess 20% of the biological activity of diperoxovanadate.

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Novel therapeutic strategies for the treatment of Type 2 diabetes

Perfetti

Barnett

Mathur

et al. 1998

Diabetes Metab. Rev.

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Diabetes mellitus is the most common endocrine disease, accounting for over 200 million people affected worldwide. It is characterized by a lack of insulin secretion and/or increased cellular resistance to insulin, resulting in hyperglycemia and other metabolic disturbances. People with diabetes suffer from increased morbidity and premature mortality related to cardiovascular, microvascular and neuropathic complications. The Diabetes Control and Complication Trial (DCCT) has convincingly demonstrated the relationship of hyperglycemia to the development and progression of complications and showed that improved glycemic control reduced these complications. Although the DCCT exclusively studied patients with Type 1 diabetes, there is ample evidence to support the belief that the same relationship between metabolic control and clinical outcome exists in patients with Type 2 diabetes. Therefore, a major effort should be made to develop and implement more effective treatment regimes. This article reviews those novel drugs that have been recently introduced for the management of Type 2 diabetes, or that have reached an advanced level of study and will soon be proposed for preliminary clinical trials. They include: (i) compounds that promote the synthesis/secretion of insulin by the beta-cell; (ii) inhibitors of the alpha-glucosidase activity of the small intestine; (iii) substances that enhance the action of insulin at the level of the target tissues; and (iv) inhibitors of free fatty acid oxidation.

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Permolybdate and Pertungstate-Potent Stimulators of Insulin Effects in Rat Adipocytes: Mechanism of Action

Cited by 77 publications

References 37 publications

Energetic Determinants of Tyrosine Phosphorylation of Focal Adhesion Proteins during Hypoxia/Reoxygenation of Kidney Proximal Tubules

Energetic Determinants of Tyrosine Phosphorylation of Focal Adhesion Proteins during Hypoxia/Reoxygenation of Kidney Proximal Tubules

Properties of Pervanadate and Permolybdate

Novel therapeutic strategies for the treatment of Type 2 diabetes

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