Advanced glycation endproducts stimulate the MAP‐kinase pathway in tubulus cell line LLC‐PK<sub>1</sub>

Simm, Andreas; Münch, Gerald; Seif, F. J.; Schenk, Oliver; Heidland, A.; Richter, Hedwig; Vamvakas, Spiridou; Schinzel, Reinhard

doi:10.1016/s0014-5793(97)00644-3

Cited by 74 publications

(48 citation statements)

References 28 publications

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“…These receptors probably exist to facilitate the uptake and clearance of these glycosylated proteins but when stimulated to excess, they can mediate adverse cellular events. Recently it has been shown that ligand binding to RAGE activates MAP kinases [15, 64,65]. The responses downstream of MAP kinase activation by RAGE have yet to be identified but earlier considerations suggest a phenotypic shift or proliferation.…”

Section: Sorbitol Pathwaymentioning

confidence: 99%

Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

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The results of the Diabetes Control and Complications Trial [1] emphatically confirmed the heroic studies of Jean Pirart [2±4], showing that poor control of glycaemia in Type I (insulin-dependent) diabetes mellitus predisposes patients to chronic complications. This has led to the tacit assumption that glucose, at supranormal concentrations, is the agent of damage. Participation of hypoinsulinaemia or other manifestations of poor control cannot be discounted but glucose itself certainly has the capacity to disturb biosystems. It can do this in a variety of ways, so that hypotheses to explain specific complications ± retinopathy, nephropathy and neuropathy ± starting from high glucose are tenable, testable and, therefore, useful.Figure 1 presents a simple generic plan by which complications develop. It usefully discriminates between metabolic effects of glucose on the target cells showing the complication and the exacerbating effect of independent accelerators, such as arterial hypertension in diabetic nephropathy. Not all independent accelerators have, however, as clearly defined a rela- Diabetologia (1999) AbstractThe damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses ± the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress ± and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999

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Section: Sorbitol Pathwaymentioning

confidence: 99%

Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

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“…AGEs activate intracellular signal transduction systems with the consecutive generation of free oxygen radicals, leading to activation of the redoxsensitive transcription factor NF-B and induction of NF-B-controlled genes such as interleukin-6 (IL-6) (54, 56,59,63,64 -76). AGEs activate various intracellular second messengers, including mitogen-activated protein kinase (33,34,54,57,59,63,(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77). Furthermore, the nitric oxide synthase activity is inhibited by early glycation end products as well as AGEs in rabbit tubular epithelial cells in vitro (57,78).…”

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confidence: 99%

Activation of Tubular Epithelial Cells in Diabetic Nephropathy

et al. 2002

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Previous studies have shown that renal function in type 2 diabetes correlates better with tubular changes than with glomerular pathology. Since advanced glycation end products (AGEs; AGE-albumin) and in particular carboxymethyllysine (CML) are known to play a central role in diabetic nephropathy, we studied the activation of nuclear factor B (NF-B) in tubular epithelial cells in vivo and in vitro by AGE-albumin and CML. Urine samples from healthy control subjects (n ‫؍‬ 50) and type 2 diabetic patients (n ‫؍‬ 100) were collected and tested for excretion of CML and the presence of proximal tubular epithelial cells (pTECs). CML excretion was significantly higher in diabetic patients than in healthy control subjects (P < 0.0001) and correlated with the degree of albuminuria (r ‫؍‬ 0.7, P < 0.0001), while there was no correlation between CML excretion and HbA 1c (r ‫؍‬ 0.03, P ‫؍‬ 0.76). Urine sediments from 20 of 100 patients contained pTECs, evidenced by cytokeratin 18 positivity, while healthy control subjects (n ‫؍‬ 50) showed none (P < 0.0001). Activated NF-B could be detected in the nuclear region of excreted pTECs in 8 of 20 patients with pTECs in the urine sediment (40%).

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“…Interaction of AGEs with endothelial surface RAGE generates intracellular oxidative stress, resulting in activation of nuclear factor κB transcription factor [35]. Moreover, mitogen-activated protein kinase and its downstream protein, the AP-1 transcription factor, might also be activated by AGE in tubular cells [36]. However, the present study is the first demonstration that the JAK\STAT pathway is associated with mitogenic response to AGE in renal interstitial fibroblasts.…”

Section: Discussionmentioning

confidence: 70%

Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells

Huang

Guh

Hung

et al. 1999

Biochemical Journal

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Advanced glycation end product (AGE) is important in the pathogenesis of diabetic nephropathy, which is characterized by cellular hypertrophy/hyperplasia leading to renal fibrosis. However, the signal transduction pathways of AGE remain poorly understood. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway has been associated with cellular proliferation in some extra-renal cells. Because interstitial fibroblast proliferation might be important in renal fibrosis, we studied the role of the JAK/STAT pathway in NRK-49F (normal rat kidney fibroblast) cells cultured in AGE/BSA and non-glycated BSA. We showed that AGE dose-dependently (10-200 μg/ml) increased cellular mitogenesis in NRK-49F cells at 5 and 7 days. However, cellular mitogenesis was unaffected by the simultaneous presence of BSA. Regarding the JAK/STAT pathway, AGE (100 μg/ml) induced tyrosine phosphorylation of JAK2 (but not JAK1, JAK3 or TYK2) at 15-60 min; it also induced the tyrosine phosphorylation of STAT1 and STAT3 at 1-2 h and 0.5-4 h respectively. Being a transcription factor, AGE also increased the DNA-binding activities of STAT1 and STAT3 AG-490 (a specific JAK2 inhibitor) (5 μM) inhibited tyrosine phosphorylation of JAK2 and the DNA-binding activities of STAT1 and STAT3. The same results were obtained by using specific ‘decoy’ oligodeoxynucleotides (ODNs) that prevented STAT1 and STAT3 from binding to DNA. Meanwhile, the STAT1 or STAT3 decoy ODN and AG-490 were effective in reversing AGE-induced cellular mitogenesis. We concluded that the JAK2-STAT1/STAT3 signal transduction pathway is necessary for AGE-induced cellular mitogenesis in NRK-49F cells.

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Advanced glycation endproducts stimulate the MAP‐kinase pathway in tubulus cell line LLC‐PK₁

Cited by 74 publications

References 28 publications

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Activation of Tubular Epithelial Cells in Diabetic Nephropathy

Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells

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Advanced glycation endproducts stimulate the MAP‐kinase pathway in tubulus cell line LLC‐PK1

Cited by 74 publications

References 28 publications

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Activation of Tubular Epithelial Cells in Diabetic Nephropathy

Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells

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Advanced glycation endproducts stimulate the MAP‐kinase pathway in tubulus cell line LLC‐PK₁