Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

Flyvbjerg, Allan

doi:10.1007/s001250051515

Cited by 196 publications

(180 citation statements)

References 76 publications

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“…GH and IGF-I were initially shown to affect the diabetic kidney by increasing glomerular filtration rates and renal plasma flow, resulting in the typical enlarged kidney seen in patients with recent onset of diabetes (Flyvbjerg, 2000). Similar changes were seen in experimental animal models of diabetes, particularly of the type 1 variety.…”

Section: Igfbpsmentioning

confidence: 82%

The Insulin‐Like Growth Factor System

Roith

2003

Journal of Diabetes Research

167

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The insulin-like growth factor (IGF) system in ubiquitous and plays a role in every tissue of the body. It is comprised of ligands, receptors and binding proteins, each with specific functions. While it plays an essential role in embryonic and post-natal development, the IGF system is also important in normal adult physiology. There are now numerous examples of diseases such as diabetes, cancer, and malnutrition in which the IGF system is a major player and, not surprisingly, there are attempts to affect these disorders by manipulating the system.

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Section: Igfbpsmentioning

confidence: 82%

The Insulin‐Like Growth Factor System

Roith

2003

Journal of Diabetes Research

167

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“…Recruitment of these cytokines leads to overexpression of their receptors and activation of their corre- sponding signaling pathways, such as phosphorylation of IRS-1 and Erk1/2 for IGF-1 and of Smad for TGF-␤1. These phenomena are paralleled by the progression of glomerulosclerosis strongly suggesting a link of causality that is sustained by the beneficial effects of their blockades (20,60,69). Reducing hyperglycemia with insulin not only reverses both receptor overexpression and activation of these signaling pathways, but it also delays formation of renal lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the antihypertrophic effect of BK in vivo on the renal vasculature in mice has been also reported (67). Therefore, the present study was designed to investigate the effect ACEI as well as the involvement of B2-kinin receptor inhibition on the expression of several growth factor receptors involved in the development of diabetic glomerulosclerosis (20). …”

mentioning

confidence: 99%

“…Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDGF) that are involved in the early onset of diabetesinduced renal changes. In addition to the upregulation and activation of growth factor and cytokine receptors, the activation of the renal renin-angiotensin system (RAS) and oxidative stress have been identified as critical events that largely contribute to worsening DN (7).…”

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confidence: 99%

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ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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Tack I, Girolami J-P. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol 293: F1083-F1092, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00401.2006 is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-␤1 (TGF-␤-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-␤-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.angiotensin-converting enzyme inhibitor; oxidative stress; glutathione peroxidase activity; diabetes DIABETIC NEPHROPATHY (DN) causes the majority of end-stage renal diseases throughout the world (54). It was initially believed that elevated blood glucose was the major cause of renal damage in both type 1 and 2 diabetes. However, several clinical studies have demonstrated that strict glycemic control is not sufficient to prevent the progression of renal dysfunction and the development of glomerular lesions. The mechanisms underlying the progression of diabetic kidney disease are intricate and still not completely understood. Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDG...

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“…DURING DIABETIC NEPHROPATHY (DN), hyperglycemia triggers numerous deleterious biological responses, such as extracellular matrix protein secretion, cell proliferation, and growth factor activation, including IGF-1, PDGF-BB, VEGF, and their receptors (11,23,41,53,56). These growth factors are suggested to be involved in the hyperplasia and extracellular matrix accumulation associated with acute or chronic glomerulosclerosis (1,8,23,36,46).…”

mentioning

confidence: 99%

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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Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

Cited by 196 publications

References 76 publications

The Insulin‐Like Growth Factor System

The Insulin‐Like Growth Factor System

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

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