Protein Tyrosine Phosphatase 1B Inhibition Protects against Podocyte Injury and Proteinuria

Kumagai, Toru; Baldwin, Carliss Y.; Aoudjit, Lamine; Nezvitsky, Lisa; Robins, Richard; Jiang, Ruihua; Takano, Tomoko

doi:10.1016/j.ajpath.2014.05.005

Cited by 29 publications

(33 citation statements)

References 64 publications

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“…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: 92%

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: Knockdown Of Pten But Not Ptp1b Rescues Insulin Sensitivitmentioning

confidence: 92%

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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“…Mice expressing Cre recombinase under the control of podocin promoter on the C57Bl/6J background were purchased from Jackson Laboratories. PTP1B floxed mice were bred to podocin-Cre mice to generate mice with podocyte-specific PTP1B disruption as described [25, 26]. Genotyping for the PTPN1 floxed allele and Cre was performed by polymerase chain reaction using DNA extracted from tails.…”

Section: Methodsmentioning

confidence: 99%

“…PTP1B podocyte deficiency or pharmacological inhibition attenuate complement-mediated glomerular injury [25] and protect against proteinuria [26]. Moreover, several PTP1B substrates are implicated in podocyte function.…”

Section: Introductionmentioning

confidence: 99%

Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury

et al. 2017

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Objective Diabetic nephropathy is one of the most devastating complications of diabetes, and growing evidence implicates podocyte dysfunction in disease pathogenesis. The objective of this study was to investigate the contribution of protein tyrosine phosphatase 1B (PTP1B) in podocytes to hyperglycemia-induced renal injury. Methods To determine the in vivo function of PTP1B in podocytes we generated mice with podocyte-specific PTP1B disruption (hereafter termed pod-PTP1B KO). Kidney functions were determined in control and pod-PTP1B KO mice under normoglycemia and high-fat diet (HFD)- and streptozotocin (STZ)-induced hyperglycemia. Results PTP1B expression increased in murine kidneys following HFD and STZ challenges. Under normoglycemia control and pod-PTP1B KO mice exhibited comparable renal functions. However, podocyte PTP1B disruption attenuated hyperglycemia-induced albuminuria and renal injury and preserved glucose control. Also, podocyte PTP1B disruption was accompanied with improved renal insulin signaling and enhanced autophagy with decreased inflammation and fibrosis. Moreover, the beneficial effects of podocyte PTP1B disruption in vivo were recapitulated in E11 murine podocytes with lentiviral-mediated PTP1B knockdown. Reconstitution of PTP1B in knockdown podocytes reversed the enhanced insulin signaling and autophagy suggesting that they were likely a consequence of PTP1B deficiency. Further, pharmacological attenuation of autophagy in PTP1B knockdown podocytes mitigated the protective effects of PTP1B deficiency. Conclusions These findings demonstrate that podocyte PTP1B deficiency attenuates hyperglycemia-induced renal damage and suggest that PTP1B may present a therapeutic target in renal injury.

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“…6) Furthermore, PTP1B has been implicated in tumorigenesis, podocyte injury, endothelial dysfunction, and retinal light damage. 1,2,[7][8][9] Based on this background, PTP1B has been attracting attention as a potential therapeutic target and a large number of PTP1B inhibitors have been reported as candidates for anti-diabetic and anti-obesity drugs. 1,[10][11][12] Classically, some types of vanadates have been shown to inhibit PTP1B and exert insulinomimetic actions.…”

mentioning

confidence: 99%

“…These inhibitors may be effective against not only diabetes and obesity, but also cancer, neuroinflammation, and retinal and renal failure. 1,2,[7][8][9] Reported allosteric inhibitors consist of two or more aromatic rings connected via acyl, ether, or alkyl linkers, and exhibit relatively weak activity. 11) In the present study, we synthesized a series of benzoylsulfonamide derivatives with a linker and aromatic ring.…”

mentioning

confidence: 99%

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

Morishita

Shoji

Tanaka

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of benzoylsulfonamide derivatives were synthesized and biologically evaluated. Among them, 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzamide (compound 18K) was identified as a protein tyrosine phosphatase 1B (PTP1B) inhibitor with potent and selective inhibitory activity against PTP1B (IC 50 0.25 µM). Compound 18K functioned as a non-competitive inhibitor and bound to the allosteric site of PTP1B. It also showed high oral absorption in mice (the maximum drug concentration (C max ) 45.5 µM at 30 mg/kg), rats (C max 53.6 µM at 30 mg/kg), and beagles (C max 37.8 µM at 10 mg/kg), and significantly reduced plasma glucose levels at 30 mg/kg/d (per os (p.o.)) for one week with no side effects in db/db mice. In conclusion, the substituted benzoylsulfonamide was shown to be a novel scaffold of a noncompetitive and allosteric PTP1B inhibitor, and compound 18K has potential as an efficacious and safe antidiabetic drug as well as a useful tool for investigations of the physiological and pathophysiological effects of allosteric PTP1B inhibition.Key words benzoylsulfonamide; protein tyrosine phosphatase 1B; allosteric inhibitor; non-competitive inhibitor; db/db mouse; Sprague-Dawley rat In various cellular signaling pathways, protein tyrosine kinases (PTKs) mediate the phosphorylation of tyrosine residues in a number of proteins, while protein tyrosine phosphatases (PTPs) de-phosphorylate phosphorylated tyrosine.

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Protein Tyrosine Phosphatase 1B Inhibition Protects against Podocyte Injury and Proteinuria

Cited by 29 publications

References 64 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

Protein tyrosine phosphatase 1B deficiency in podocytes mitigates hyperglycemia-induced renal injury

Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

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