NF- B activation and overexpression of regulated genes in human diabetic nephropathy

Mezzano, Sergio; Aros, Claudio; Droguett, Alejandra; Burgos, M. Eugenia; Ardiles, Leopoldo; Flores, Claudio; Schneider, Herman; Ruíz-Ortega, Marta; Egido, Jesús

doi:10.1093/ndt/gfh207

Cited by 356 publications

(294 citation statements)

References 18 publications

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“…Experimental and clinical studies have demonstrated that DN exhibits signs of inflammation, such as increased expression of adhesion molecules (44), chemokines (45), growth factors (46), and proinflammatory cytokines, including TNF-␣, in renal tissue (37)(38)(39)(40). In addition, the enhanced passage of proteins across the glomerular barrier as a result of any insult to the filtration compartment exerts deleterious effects on the kidney in part by eliciting an inflammatory reaction with an increased gene expression for several proinflammatory molecules (47,48).…”

Section: Discussionmentioning

confidence: 99%

Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade

Navarro¹,

Mora²,

Muros³

et al. 2005

Journal of the American Society of Nephrology

115

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Despite the beneficial effects of blockade of the renin-angiotensin system in diabetic nephropathy (DN), albuminuria and progression of renal disease are not completely halted by these agents. Therefore, it is necessary to explore potential antiproteinuric and renoprotective effects of innovative therapeutic approaches. This study tested the hypothesis that the combination of pentoxifylline (PTF) with angiotensin II receptor blockers in normotensive patients with type 2 diabetes produces an additive antiproteinuric effect. Sixty-one patients with DN and residual albuminuria despite treatment with the recommended doses of ARB for >1 yr were randomly assigned to receive the addition of 1200 mg of PTF daily (n ‫؍‬ 30) or to a control group (n ‫؍‬ 31). Baseline characteristics were similar between groups, and correlation analysis showed a significant association between urinary albumin excretion (UAE) and urinary TNF-␣ (R ‫؍‬ 0.53, P < 0.001). After 4 mo, albuminuria showed a significant decrease in patients who received PTF, from 900 mg/24 h (466 to 1542 mg/d) to 791 mg/24 h (309 to 1400 mg/d; P < 0.001), whereas no significant changes were observed in the control group: 920 mg/24 h (450 to 1489 mg/d) at baseline, and 900 mg/24 h (428 to 1800 mg/d) at the end of the study. The mean percentage variation of UAE in the treatment and control groups was ؊16.7 and 5.5%, respectively (between-group comparison, P < 0.001). This additive antiproteinuric effect was not dependent on changes in BP or metabolic control. However, both serum and urinary levels of TNF-␣ also decreased in patients who received PTF, from 6.4 pg/ml (2.1 to 9.7) and 16 pg/mg (8 to 29) at baseline to 4.6 pg/ml (0.4 to 9) and 14.2 pg/mg (3 to 26) at the end of the study, respectively (P < 0.01), without significant variations in control patients. Moreover, regression analysis at the end of the study showed a correlation between the change in UAE and the change in urinary TNF-␣ in patients who were treated with PTF (R ‫؍‬ 0.49, P < 0.001). In conclusion, administration of PTF to patients who have type 2 diabetes and are under long-term treatment with an ARB produces a significant additive antiproteinuric effect associated with a reduction of urinary TNF-␣ excretion.

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Section: Discussionmentioning

confidence: 99%

Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade

Navarro¹,

Mora²,

Muros³

et al. 2005

Journal of the American Society of Nephrology

115

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“…In general, NF-B activates in macrophages and glomerular (including podocytes in proteinuric diseases) and tubular parenchymal cells and correlates with parameters of severity of disease such as proteinuria or inflammation. 59,[61][62][63][64][65] These data have been interpreted as supportive for the role of NF-B in promoting inflammation; however, inflammation itself will promote NF-B activation, and because these data are descriptive, the precise role of the various NF-B complexes in human kidney injury remains uncertain. Functional evidence of NF-B activation has been obtained by transcriptomics-based pathway mapping 66 ; in progressive diabetic nephropathy, there is upregulation of 54 of 138 known NF-B targets with special enrichment in NF-B/IRFF module target genes.…”

Section: Nf-b Activation In Experimental and Human Renal Diseasementioning

confidence: 99%

NF-κB in Renal Inflammation

Sanz¹,

Sanchez-Niño²,

Ramos³

et al. 2010

Journal of the American Society of Nephrology

504

379

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“…20 -23 Activation of renal NF-B has been described in human kidney diseases, associated to proinflammatory factors overexpression. 24,25 We have now investigated whether CTGF could modulate the inflammatory response in the kidney and the mechanisms underlying this process, evaluating the involvement of the NF-B signaling pathway. …”

mentioning

confidence: 99%

CTGF Promotes Inflammatory Cell Infiltration of the Renal Interstitium by Activating NF-κB

Sánchez-López¹,

Rayego²,

Rodrigues‐Díez³

et al. 2009

Journal of the American Society of Nephrology

118

100

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Connective tissue growth factor (CTGF) is an important profibrotic factor in kidney diseases. Blockade of endogenous CTGF ameliorates experimental renal damage and inhibits synthesis of extracellular matrix in cultured renal cells. CTGF regulates several cellular responses, including adhesion, migration, proliferation, and synthesis of proinflammatory factors. Here, we investigated whether CTGF participates in the inflammatory process in the kidney by evaluating the nuclear factor-kappa B (NF-B) pathway, a key signaling system that controls inflammation and immune responses. Systemic administration of CTGF to mice for 24 h induced marked infiltration of inflammatory cells in the renal interstitium (T lymphocytes and monocytes/macrophages) and led to elevated renal NF-B activity. Administration of CTGF increased renal expression of chemokines (MCP-1 and RANTES) and cytokines (INF-␥, IL-6, and IL-4) that recruit immune cells and promote inflammation. Treatment with a NF-B inhibitor, parthenolide, inhibited CTGF-induced renal inflammatory responses, including the up-regulation of chemokines and cytokines. In cultured murine tubuloepithelial cells, CTGF rapidly activated the NF-B pathway and the cascade of mitogen-activated protein kinases, demonstrating crosstalk between these signaling pathways. CTGF, via mitogen-activated protein kinase and NF-B activation, increased proinflammatory gene expression. These data show that in addition to its profibrotic properties, CTGF contributes to the recruitment of inflammatory cells in the kidney by activating the NF-B pathway.

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NF- B activation and overexpression of regulated genes in human diabetic nephropathy

Abstract: The activation of NF-kappaB and the transcription of certain pro-inflammatory chemokines in tubular epithelial cells are markers of progressive DN. Proteinuria might be one of the main factors inducing the observed pro-inflammatory phenotype.

Cited by 356 publications

References 18 publications

Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade

Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade

NF-κB in Renal Inflammation

CTGF Promotes Inflammatory Cell Infiltration of the Renal Interstitium by Activating NF-κB

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