Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-α and inducible nitric oxide synthase in diabetic rat glomeruli

Sugimoto, Hikaru; Shikata, Kenichi; Wada, Jun; Horiuchi, Seikoh; Makino, Hírofumi

doi:10.1007/s001250051241

Cited by 152 publications

(117 citation statements)

References 14 publications

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“…Values were 88 ± 16 vs. 16 ± 2 relative fluorescence U/mg protein, as assessed fluorometrically, 43.7 ± 2.3 vs. 4.6 ± 0.5 AGE U/mg protein, as assessed by the ELISA using the polyclonal antibody, and 51.9 ± 3.2 vs. 4.8 ± 1.0 AGE U/mg protein, as assessed by the ELISA using the monoclonal antibody (P < 0.001 in all cases). These values are similar to (or lower than) those detected in the AGE preparations used in previous in vitro and in vivo studies (3,4,27,28), and they are also comparable to AGE levels observed in sera of diabetic patients (26,29) and in kidneys of experimental diabetic animals (30). Coincubation of BSA with 0.1 mol/l AM almost completely prevented AGE formation; AGE levels were only 50% higher than those in native BSA.…”

Section: Experimental Designsupporting

confidence: 87%

The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression.

et al. 2000

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Nonenzymatic glycation has been implicated in the pathogenesis of the dysregulated tissue remodeling that characterizes diabetic glomerulopathy, via the formation of advanced glycation end products (AGEs) and their binding to cell surface receptors. Several AGEbinding proteins have been identified so far, including p60, p90, and the adhesive and growth-regulating lectin galectin-3 (Gal-3), the components of the so-called AGEreceptor complex. This study aimed to evaluate the mesangial expression of the AGE-receptor complex and its modulation by the diabetic milieu, both in vivo, in nondiabetic versus streptozotocin-induced diabetic rats, and in vitro, in mesangial cells exposed to either normal glucose (NG) levels (5.5 mmol/l), as compared with high glucose (HG) levels (30 mmol/l) and iso-osmolar mannitol (M), or to native bovine serum albumin (BSA), as compared with glycated BSA with AGE formation (BSA-AGE) and glycated BSA in which AGE formation was prevented by aminoguanidine (BSA-AM). In vivo, Gal-3 protein and mRNA were not detectable in glomeruli from nondiabetic rats until 12 months after initiating the study. On the contrary, in diabetic rats, Gal-3 expression was observed at 2 months of disease duration, and it increased thereafter. Both p60 and p90 immunoreactivities were observed at the glomerular level with slightly increased expression of p90, but not p60, in diabetic versus nondiabetic animals. In vitro, Gal-3 was not detectable in mesangial cells cultured in NG (although it became evident after a certain number of passages in culture), whereas Gal-3 was detectable in cells grown on BSA. Prolonged exposure (2-4 weeks) of mesangial cells to HG but not to M, as well as growing cells on BSA-AGE and, to a lesser extent, BSA-AM, induced or significantly increased the expression of Gal-3, both protein (up to 2.65-fold) and mRNA (up to 3.10-fold) and its secretion in the medium (by ~50%). Both p60 and p90 were demonstrated in mesangial cells under NG conditions, and the expression of p90, but not p60, was upregulated by ~20% by HG or BSA-AGE. These results indicate that 1) under basal conditions, Gal-3, unlike p90 and p60, is not detectable in the mesangium but becomes expressed with aging and 2) the diabetic milieu induces or upregulates Gal-3 production, whereas it increases only slightly the expression of p90, but not p60. Gal-3 expression or overexpression may modulate the AGE-receptor-mediated events by modifying the function of the AGE-receptor complex. Additionally, it may exert direct effects on tissue remodeling by virtue of its adhesive and growthregulating properties.

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Section: Experimental Designsupporting

confidence: 87%

The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression.

et al. 2000

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“…Recent studies have highlighted the potential relevance of TNF-␣ in the development and progression of renal lesion in diabetes. Endothelial, mesangial, glomerular, and tubular epithelial cells are able to produce cytokines, and diverse experimental works have demonstrated that renal mRNA levels for TNF-␣ are significantly increased in diabetic rats compared with control rats (37)(38)(39)(40). From a pathogenic perspective, it is particularly relevant that the findings of experimental studies show that increased urinary as well as renal interstitial concentrations of TNF-␣ precede the rise in albuminuria (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…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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“…It is involved in renal damage in experimental model [114,115] Serum TNF α level are increased in diabetic patient [118] Urinary TNF α level and renal TNF α correlates with urinary albumin excretion [118] ROLE OF TNF α [124] In diabetic rat model study anti-TNF α reduces urinary protein, prevented sodium retention and renal hypertrophy [124] Infliximab -a chimeric mmonoclonal antibody directed against TNF α reduces albuminuria and urinary TNF α level. [117] Also anti-TNF α improved glucose tolerance and control in type 2 diabetic patient [116] www.wjpps.com Vol 6, Issue 7, 2017.…”

Section: Stimuli For Tnf α-Ages Angioiimentioning

confidence: 99%

Drugs for Diabetic Nephropathy- Full Review

Soni¹

2017

WJPPS

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Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-α and inducible nitric oxide synthase in diabetic rat glomeruli

Cited by 152 publications

References 14 publications

The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression.

The diabetic milieu modulates the advanced glycation end product-receptor complex in the mesangium by inducing or upregulating galectin-3 expression.

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

Drugs for Diabetic Nephropathy- Full Review

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