Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat

Hopfner, Rob L; Misurski, Derek; Wilson, Thomas W.; McNeill, J. Robert; Gopalakrishnan, Venkat

doi:10.1007/s001250051057

Cited by 27 publications

(11 citation statements)

References 41 publications

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“…With the present study we demonstrate that STZ-induced diabetes is a model of insulin-dependent diabetes (type 1) and that STZ-dependent vascular complications are probably not associated with systemic toxic side effects but strictly depend on insulin deficiency. These findings are in good agreement with previous reports on insulin replacement therapy, in which insulin completely normalized the adverse effects of STZ on vascular responsiveness and vascular superoxide formation [28], on blood glucose levels and weight gain [27] as well as on STZ-triggered vasoconstrictive responses to both endothelin-1 and methoxamine [50]. More support for our concept came from Higashi et al [29], who reported that retinal blood flow is decreased in diabetic rats and normalized by insulin therapy, although these authors used a different protocol for induction of diabetes and found that vascular abnormalities are not completely reversed by short-term insulin therapy upon long-term untreated diabetes.…”

Section: Discussionsupporting

confidence: 82%

Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency

Oelze¹,

Knorr²,

Schuhmacher³

et al. 2011

J Vasc Res

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Objective: In previous studies we and others have shown that streptozotocin (STZ)-induced diabetes in rats is associated with vascular oxidative stress and dysfunction. In the present study, we sought to determine whether vascular dysfunction and oxidative stress strictly depend on insulin deficiency. Methods: The effects of insulin (2.5 U/day s.c., 2 weeks) therapy on vascular disorders in STZ-induced (60 mg/kg i.v., 8 weeks) diabetes mellitus (type I) were studied in Wistar rats. The contribution of NADPH oxidase to overall oxidative stress was investigated by in vivo (30 mg/kg/day s.c., 4 days) and in vitro treatment with apocynin. Results: Insulin therapy completely normalized blood glucose, body weight, vascular dysfunction and oxidative stress as well as increased cardiac reactive oxygen and nitrogen species formation in diabetic rats, although diabetes was already established for 6 weeks before insulin therapy was started for the last 2 weeks of the total treatment interval. Apocynin normalized cardiac NADPH oxidase activity, and L-NAME effects suggest a role for uncoupled endothelial nitric oxide synthase in diabetic vascular complications. Conclusions: Our findings indicate that STZ-induced diabetes is a model of insulin-dependent diabetes (type 1) and that cardiovascular complications are probably not associated with systemic toxic side effects of STZ.

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Section: Discussionsupporting

confidence: 82%

Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency

Oelze¹,

Knorr²,

Schuhmacher³

et al. 2011

J Vasc Res

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“…In the STZ model, injection of STZ destroys the insulin secreting b-cells of the pancreas and these rats develop severe chronic hyperglycemia analogous to type 1 (insulin-dependent) diabetes mellitus [24]. In contrast with other models, blood pressure in these rats is reduced beginning at 2 weeks after injection [25].…”

Section: Discussionmentioning

confidence: 98%

Effects of hyperglycemia on the modulation of vascular function by perivascular adipose tissue

Lee

Lü²,

Su³

et al. 2009

Journal of Hypertension

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“…Vascular elaboration of endothelin promotes glomerular damage by augmenting vasoconstriction, glomerular permeability, mesangial cell proliferation, and extracellular matrix production (22). In support of this view, it has been reported that plasma endothelin antigen and vascular cell endothelin mRNA are increased in both humans with diabetes and in STZ-treated rats (27). Moreover, increased plasma endothelin levels in diabetes are associated with an elevated risk of microvascular complications, suggesting a possible link between endothelin and microangiopathy (1,18).…”

Section: Role Of Endothelin Signaling In Diabetesmentioning

confidence: 90%

Role of the JAK/STAT signaling pathway in diabetic nephropathy

Marrero

Banes-Berceli

Stern

et al. 2006

American Journal of Physiology-Renal Physiology

186

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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Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat

Cited by 27 publications

References 41 publications

Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency

Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency

Effects of hyperglycemia on the modulation of vascular function by perivascular adipose tissue

Role of the JAK/STAT signaling pathway in diabetic nephropathy

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