Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation

Landau, Daniel; Eshet, Renanah; Troib, Ariel; Gurman, Yotam; Chen, Yu; Rabkin, Ralph; Segev, Yael

doi:10.1007/s12020-009-9190-2

Cited by 25 publications

(26 citation statements)

References 42 publications

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“…Hyperglycemia has been shown by other investigators to enhance IGF-I downstream signaling in diabetic kidneys, even though IGF-I receptor activation is not increased. This suggests that in diabetes, there is increased renal sensitivity to IGF-I stimulation (39). Therefore, although we did not quantify changes in IGF-I signaling in this animal model, we conclude based on previous results that it is likely that the antibody inhibited IGF-I signaling in renal endothelial cells in the diabetic animals.…”

Section: Discussionmentioning

confidence: 82%

Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

et al. 2014

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Hyperglycemia stimulates secretion of αVβ3 ligands from vascular cells, including endothelial cells, resulting in activation of the αVβ3 integrin. This study determined whether blocking ligand occupancy of αVβ3 would inhibit the development of diabetic nephropathy. Ten diabetic pigs received an F(ab)2 fragment of an antibody directed against the extracellular domain of the β3-subunit, and 10 received a control IgG F(ab)2 for 18 weeks. Nondiabetic pigs excreted 115 ± 50 μg of protein/mg creatinine compared with control F(ab)2-treated diabetic animals (218 ± 57 μg/mg), whereas diabetic animals treated with the anti-β3 F(ab)2 excreted 119 ± 55 μg/mg (P < .05). Mesangial volume/glomerular volume increased to 21 ± 2.4% in control-treated diabetic animals compared with 14 ± 2.8% (P < .01) in animals treated with active antibody. Diabetic animals treated with control F(ab)2 had significantly less glomerular podocin staining compared with nondiabetic animals, and this decrease was attenuated by treatment with anti-β3 F(ab)2. Glomerular basement membrane thickness was increased in the control, F(ab)2-treated diabetic animals (212 ± 14 nm) compared with nondiabetic animals (170 ± 8.8 nm), but it was unchanged (159.9 ± 16.4 nm) in animals receiving anti-β3 F(ab)2. Podocyte foot process width was greater in control, F(ab)2-treated, animals (502 ± 34 nm) compared with animals treated with the anti-β3 F(ab)2 (357 ± 47 nm, P < .05). Renal β3 tyrosine phosphorylation decreased from 13 934 ± 6437 to 6730 ± 1524 (P < .01) scanning units in the anti-β3-treated group. We conclude that administration of an antibody that inhibits activation of the β3-subunit of αVβ3 that is induced by hyperglycemia attenuates proteinuria and early histologic changes of diabetic nephropathy, suggesting that it may have utility in preventing the progression of this disease complication.

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Section: Discussionmentioning

confidence: 82%

Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

et al. 2014

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“…Priming of naïve T cells by DC that present high affinity antigen to the TCR in the context of costimulatory molecules overcomes this barrier by triggering chromatin decondensation. This allows transcription factors such as Stat5to bind promoters involved in T cell proliferation and cytokine expression (15). Our data show that naïve T cells in diabetic hosts are pre-activated via RAGE signaling and have an exaggerated response to initial TCR stimulation.…”

Section: Discussionmentioning

confidence: 99%

Chromatin Decondensation and T Cell Hyperresponsiveness in Diabetes-Associated Hyperglycemia

Martínez

Vallerskog

West

et al. 2014

The Journal of Immunology

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Diabetes is linked to increased inflammation and susceptibility to certain infectious diseases including tuberculosis (TB). We previously reported that aerosol TB in mice with chronic (≥12 wk) hyperglycemia features increased bacterial load, over-production of several cytokines and increased immune pathology compared to normoglycemic controls. A similar phenotype exists in human diabetics with TB. The mechanisms of increased T cell activation in diabetes are unknown. In the current study, we tested the hypothesis that hyperglycemia modifies the intrinsic responsiveness of naïve T cells to TCR stimulation. Purified T cells from chronically hyperglycemic (HG) mice produced higher levels of Th1, Th2 and Th17 cytokines and proliferated more than T cells from normoglycemic controls after anti-CD3e or antigen stimulation. In this way, naïve T cells from HG mice resembled antigen-experienced cells although CD44 expression was not increased. Chromatin decondensation, another characteristic of antigen-experienced T cells, was increased in naïve T cells from HG mice. That phenotype depended on expression of the receptor for advanced glycation end products (RAGE) and could be reversed by inhibiting p38 MAPK. Chromatin decondensation and hyperresponsiveness to TCR stimulation persisted following transfer of T cells from HG mice into normoglycemic mice. We propose that chronic hyperglycemia causes RAGE-mediated epigenetic modification of naïve T cells leading to p38 MAPK-dependent chromatin decondensation. This pre-activation state facilitates transcription factor access to DNA, increasing cytokine production and proliferation following TCR stimulation. This mechanism may contribute to pathological inflammation associated with diabetes and might offer a novel therapeutic target.

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“…However, FLCN has been linked to a number of additional signal transduction pathways (BHD Foundation, 2012). Most studies available focused on a modulation of mTOR signaling through FLCN (Sarbassov et al, 2005;Landau et al, 2009). FLCN has two major interaction partners -FNIP1 and FNIP2 -through which it appears to interact with AMP-activated protein kinase (AMPK) (Baba et al, 2006;Hasumi et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Loss of the Birt–Hogg–Dubé gene product folliculin induces longevity in a hypoxia‐inducible factor–dependent manner

et al. 2013

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SummarySignaling through the hypoxia-inducible factor hif-1 controls longevity, metabolism, and stress resistance in Caenorhabditis elegans. Hypoxia-inducible factor (HIF) protein levels are regulated through an evolutionarily conserved ubiquitin ligase complex. Mutations in the VHL gene, encoding a core component of this complex, cause a multitumor syndrome and renal cell carcinoma in humans. In the nematode, deficiency in vhl-1 promotes longevity mediated through HIF-1 stabilization. However, this longevity assurance pathway is not yet understood. Here, we identify folliculin (FLCN) as a novel interactor of the hif-1/vhl-1 longevity pathway. FLCN mutations cause Birt-HoggDub e syndrome in humans, another tumor syndrome with renal tumorigenesis reminiscent of the VHL disease. Loss of the C. elegans ortholog of FLCN F22D3.2 significantly increased lifespan and enhanced stress resistance in a hif-1-dependent manner. F22D3.2, vhl-1, and hif-1 control longevity by a mechanism distinct from insulin-like signaling. Daf-16 deficiency did not abrogate the increase in lifespan mediated by flcn-1. These findings define FLCN as a player in HIF-dependent longevity signaling and connect organismal aging, stress resistance, and regulation of longevity with the formation of renal cell carcinoma.

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Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation

Cited by 25 publications

References 42 publications

Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

Chromatin Decondensation and T Cell Hyperresponsiveness in Diabetes-Associated Hyperglycemia

Loss of the Birt–Hogg–Dubé gene product folliculin induces longevity in a hypoxia‐inducible factor–dependent manner

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