Activation of mesangial cells by the phosphatase inhibitor vanadate. Potential implications for diabetic nephropathy.

Wenzel, Ulrich; Fouqueray, Bruno; Biswas, Purba; Grandaliano, Giuseppe; Choudhury, Goutam Ghosh; Abboud, Hanna E.

doi:10.1172/jci117774

Cited by 30 publications

(15 citation statements)

References 47 publications

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“…The increased phosphorylation of glomerular ERK1/2 at an early phase of STZ-induced diabetes was also observed by Awazu et al (5) ascribed the diabetes-induced activation of ERK1/2 to decreased phosphatase activity and MKP-1 protein expression. This hypothesis is further supported by the fact that tyrosine phosphatase inhibition with OV mimics the diabetic phenotype in mesangial cells, i.e., increased cell proliferation, activation of protein kinase C, tyrosine phosphorylation of intracellular proteins, and induction of PDGF-B chain gene expression (52). In addition, we now demonstrate that hyperglycemia plays a primary role in glomerular ERK1/2 phosphorylation and oxidative stress during diabetes because strict glycemic control with insulin abolished MAPK phosphorylation as well as 4-HNE protein derivatization.…”

Section: Discussionmentioning

confidence: 84%

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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Several experimental data report both mitogenic and antimitogenic effects of bradykinin (BK). To conciliate these apparent opposite effects, we hypothesized that, depending on cell context activation, BK could reduce the mitogenic effect of growth factors. Therefore, in the present study we assessed the existence of possible negative cross talk between BK and potential pathogenic growth factors in freshly isolated rat glomeruli (IG). Next, we determined whether this cross talk could be pharmacologically recruited during angiotensin-converting enzyme (ACE) inhibition in the diabetic rat. In IG from normal rats, BK, via activation of the B2 kinin receptor (B2R), causes a transient stimulation of ERK1/2 phosphorylation, whereas it inhibits ERK1/2 phosphorylation induced by IGF-1, PDGF-BB, VEGF, or basic FGF. The reduction of growth factor-induced ERK1/2 phosphorylation is abolished by an inhibitor of tyrosine phosphatase. In glomeruli from diabetic rats, hyperglycemia increased the phosphorylation level of ERK-1/2 as well as oxidative stress. The reversal of these events by ACE inhibition is mediated via B2R activation. These observations are consistent with a potential therapeutic role of BK and B2R during glomerulosclerosis.

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Section: Discussionmentioning

confidence: 84%

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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“…Growth factors have a maladaptive role in the glomerular damage accompanying experimental and human glomerulonephritis. This is especially evident in diabetic nephropathy through enlargement of the glomerular remnant and mesangial matrix expansion associated with the accumulation of extracellular matrix proteins synthesized by glomerular mesangial cells (12,30,73). The vasoactive peptide ANG II, not usually considered in the context of traditional growth factors, has been implicated in both normal and diabetic cellular growth (3, 64).…”

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confidence: 99%

“…This review focuses on some of the key elements in the diabetic microenvironment, especially high glucose and the accumulation of advanced glycoxidation end products and considers their impact on ANG II and other vasoactive peptidemediated signaling events in vitro and in vivo. ANG II; high glucose; glomerular mesangial cells; advanced glycoxidation end products GLOMERULAR MESANGIAL CELLS possess both contractile and mitogenic properties and contribute to the physiological regulation of glomerular dynamics (30,73). Growth factors have a maladaptive role in the glomerular damage accompanying experimental and human glomerulonephritis.…”

mentioning

confidence: 99%

Role of the JAK/STAT signaling pathway in diabetic nephropathy

Marrero

Banes-Berceli

Stern

et al. 2006

American Journal of Physiology-Renal Physiology

189

172

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Excessive cellular growth is a major contributor to pathological changes associated with diabetic nephropathy. In particular, high glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. Glomerular mesangial cells respond to traditional growth factors, although in diabetes this occurs in the context of an environment enriched in both circulating vasoactive mediators and high glucose. For example, the vasoactive peptide ANG II has been implicated in the pathogenesis of diabetic renal disease, and recent findings suggest that high glucose and ANG II activate intracellular signaling processes, including the polyol pathway and generation of reactive oxygen species. These pathways activate the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascades in glomerular mesangial cells. Activation of the JAK/STAT signaling cascade can stimulate excessive proliferation and growth of glomerular mesangial cells, contributing to diabetic nephropathy. This review focuses on some of the key elements in the diabetic microenvironment, especially high glucose and the accumulation of advanced glycoxidation end products and considers their impact on ANG II and other vasoactive peptidemediated signaling events in vitro and in vivo. ANG II; high glucose; glomerular mesangial cells; advanced glycoxidation end products GLOMERULAR MESANGIAL CELLS possess both contractile and mitogenic properties and contribute to the physiological regulation of glomerular dynamics (30,73). Growth factors have a maladaptive role in the glomerular damage accompanying experimental and human glomerulonephritis. This is especially evident in diabetic nephropathy through enlargement of the glomerular remnant and mesangial matrix expansion associated with the accumulation of extracellular matrix proteins synthesized by glomerular mesangial cells (12,30,73). The vasoactive peptide ANG II, not usually considered in the context of traditional growth factors, has been implicated in both normal and diabetic cellular growth (3, 64). Our group has found that activation of the Janus kinase (JAK)/signal transducers and activation of transcription (STAT) pathway is essential for ANG II-induced growth of glomerular mesangial cells (4,70). In addition, we have recently shown that high glucose augments ANG II-induced activation of the JAK/STAT pathway in rat kidney glomeruli (7) and that this pathway contributes importantly to production of the cytokine TGF-␤ as well as the extracellular matrix proteins collagen IV and fibronectin (70). Furthermore, recent studies also demonstrate that high glucose induces intracellular production of reactive oxygen species (ROS) (24), which have been shown to augment ANG II-induced signaling cascades and to activate JAK and STAT proteins (63,68).Renal disease is one of the leading causes of morbidity and mortality in patients with diabetes mellitus, and ANG II has been implicated in the pathogenesis of maladaptive growth in renal tissues...

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“…26 Probably because of their insulin-like effects, vanadium compounds have recently been shown to ameliorate glucose homeostasis in type II diabetic patients and animals. 27 In view of the alarming increase in occurrence of type II diabetes, there has been considerable effort in many laboratories to identify a spectrum of suitable targets as a basis for drug design. In this context, PTPases that attenuate insulin signaling by dephosphorylating the insulin receptor have been actively pursued.…”

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confidence: 99%

Angiotensin II–Induced Insulin Resistance and Protein Tyrosine Phosphatases

Marrero

Fulton

Stepp

et al. 2004

ATVB

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Abstract-Although the importance of protein tyrosine phosphorylation by tyrosine kinases in mitogenic signaling is well-accepted, recent studies also suggest that tyrosine dephosphorylation by protein tyrosine phosphatases (PTPases) play an equally important role. For example, both angiotensin II (Ang II) and insulin are known to mediate protein tyrosine phosphorylation and dephosphorylation events. These apparently paradoxical effects of Ang II and insulin suggest that both convergent and divergent intracellular signaling cascades are stimulated downstream of their respective receptors, producing diverse cellular responses. In this review, we discuss the hypothesis that the protein tyrosine phosphatase (PTPase), PTP-1B, plays a central role in Ang II-induced insulin resistance by inhibiting activation of the insulin receptor. We hypothesize that Ang II-induced PTP-1B activation leads to dephosphorylation of the insulin receptor and that this signaling pathway underlies the maladaptive responses observed in diabetic vascular and renal tissue during type II diabetes. Key Words: insulin resistance Ⅲ angiotensin II Ⅲ PTB-1B C ardiovascular and renal complications are the leading causes of morbidity and mortality in patients with diabetes mellitus, and Ang II 1 has been implicated in the pathogenesis of maladaptive growth in both of these end organs. [1][2][3] For example, inhibition of Ang II-induced growth of vascular smooth muscle cells (VSMC) and glomerular mesangial cells (GMC) with angiotensin-converting enzyme (ACE) inhibitors and Ang II AT 1 receptor blockers (ARB) reduces cardiovascular and renal disease in diabetic patients and animal models. 4,5 High glucose has also been shown to augment Ang II-induced responses, ie, growth, contraction, Ca 2ϩ signaling, and AT 1 receptor density. Furthermore, hyperglycemia is associated with an increased incidence of neointimal hyperplasia (VSMC proliferation) and progression of nephropathy (glomerular mesangial cell [GMC] growth) in patients with diabetes. 6 The AT 1 receptor has been linked to mitogenic signaling cascades (ie, JAK/STAT, p21 ras /Raf-1/ MAP kinase, and PLC-␥1), 7 and investigators and clinicians have been able to prevent VSMC and GMC growth and proliferation by inhibiting many of these Ang II-mediated events using molecular, biochemical, and pharmacological approaches. 8,9 Both ACE inhibitors and ARB are first-line therapeutic agents for the treatment of hypertension in patients with the cardiometabolic syndrome and those with diabetes. Therapy with ACE inhibitors and ARBs reduces microvascular and macrovascular complications in diabetes and appears to improve insulin sensitivity and glucose metabolism. Several recent studies indicate that ACE inhibitor and ARB therapy also reduce the development of type II diabetes in persons with essential hypertension, a population with a high prevalence of insulin resistance. 10 ACE inhibition and ARBs have been shown to improve potential surrogates of chronic cardiovascular disease (eg, vascular compliance, endoth...

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Activation of mesangial cells by the phosphatase inhibitor vanadate. Potential implications for diabetic nephropathy.

Abstract: The metalion vanadate has insulin-like effects and has been advocated for use Clin. Invest. 1995. 95:1244-1252

Cited by 30 publications

References 47 publications

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Role of the JAK/STAT signaling pathway in diabetic nephropathy

Angiotensin II–Induced Insulin Resistance and Protein Tyrosine Phosphatases

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