Pathogenic perspectives for the role of inflammation in diabetic nephropathy

Rivero, Antonio; Mora, Carmen; Muros, Mercedes; Garcı́a, Javier Garcı́a; Herrera, H.; Navarro‐González, Juan F.

doi:10.1042/cs20080394

Cited by 169 publications

(186 citation statements)

References 176 publications

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“…Inflammation increases expression of TF, and TF induces inflammation (14). It also is well known that diabetes leads to inflammation and fibrosis (15,16). We therefore studied the renal expression of inflammatory and fibrogenic genes (Fig.…”

Section: Survival Of F1 (B6 × 129) Heterozygous Enosmentioning

confidence: 99%

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Wang

Hiller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene ( NOS3 ) have been associated with advanced nephropathy in diabetic patients and with decreased expression in tissue culture. However, direct proof that modest genetic decreases in eNOS expression worsen diabetic nephropathy is lacking. To investigate this effect, we took advantage of the hybrid vigor and genetic uniformity of the F1 progeny (eNOS +/+ , eNOS +/− , or eNOS −/− with or without diabetes) of a cross between heterozygous 129S6/SvEvTac eNOS +/− inbred females and heterozygous C57BL/6J eNOS +/− inbred males carrying the dominant Akita diabetogenic mutation Ins2 C96Y/+ . Whereas all C57BL/6J inbred eNOS −/− and eNOS +/− diabetic mice died before 5 mo, almost half of the F1 hybrid eNOS −/− and eNOS +/− diabetic mice lived until killed at 7 mo. Heterozygous eNOS +/− diabetic mice expressed ∼35% eNOS mRNA in the kidney and ∼25% glomerular eNOS protein relative to their eNOS +/+ diabetic littermates. These decreases in eNOS elevated blood pressure (BP) but not blood glucose. Urinary albumin excretion, mesangial expansion, glomerulosclerosis, mesangiolysis, and glomerular filtration rate increased in the order: eNOS +/+ Akita < eNOS +/− Akita < eNOS −/− Akita, independently of BP. Glomerular basement membrane thickening depended on increased BP. Renal expression of tissue factor and other inflammatory factors increased with the nephropathy; Nos2 also increased. Surprisingly, however, decreased eNOS expression ameliorated the increases in oxidative stress and tubulointerstitial fibrosis caused by diabetes. Our data demonstrate that a modest decrease in eNOS, comparable to that associated with human NOS3 variants, is sufficient to enhance diabetic nephropathy independently of its effects on BP.

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Section: Survival Of F1 (B6 × 129) Heterozygous Enosmentioning

confidence: 99%

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Wang

Hiller

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In this line, higher serum HMGB1 levels have been reported in individuals with coronary heart disease (17,18) or heart failure (19) compared with those without these diseases. Inflammation is involved in the development of diabetic nephropathy (20), and in this line, a recent study showed that HMGB1 may play a role in the development of diabetic nephropathy in rats (21).…”

Section: Introductionmentioning

confidence: 99%

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

Nin¹,

Ferreira²,

Schalkwijk³

et al. 2012

European Journal of Endocrinology

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Context and objective: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro-and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. Design and methods: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40G10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Results: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised bZ0.07 (95% confidence interval (CI): 0.02-0.12) and bZ0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro-and macroalbuminuria: odds ratio (OR)Z1.24 (95% CI: 0.90-1.71) and ORZ1.61 (95% CI: 1.15-2.25) respectively, P for trendZ0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. Conclusions: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes.

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“…8,9 Later, the role of inflammation and inflammatory cytokines in DN was studied over the last few years. [10][11][12][13][14][15][16] Inflammation secondary to ischemia and endothelial dysfunction was found to be associated with the development of DN. [17][18][19] Some medications were found to slow down the progression of DN through suggested antiinflammatory actions.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-to-Lymphocyte Ratio as a Predictor of Worsening Renal Function in Diabetic Patients (3-Year Follow-Up Study)

et al. 2012

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Background: Previous studies have demonstrated the role of inflammation in diabetic nephropathy (DN). Neutrophil to lymphocyte ratio (NLR) rather than other white cell parameters was found to be a useful inflammatory marker to predict adverse outcomes in medical and surgical conditions. Nevertheless, the value of NLR in predicting DN has not been elucidated. Method: An observational study included 338 diabetic patients, who were followed at our clinic between 2007 and 2009. We arranged our patients into tertiles according to their 2007 NLR. The primary outcome was continuous decrease of GFR >12 mL/min between 2007 and 2009 with the last GFR <60 mL/min. Result: The lowest NLR tertile had fewer patients (2.7%) with primary outcome (i.e., worsening renal function) compared with middle and highest NLR tertiles, which had more patients with primary outcomes (8.7% and 11.5%, respectively) with a significant p-value 0.0164. When other potential confounders were individually analyzed with NLR tertile, the NLR tertiles remained a significant predictor of poor GFR outcome in the presence of other variables (hemoglobin A1C, systolic blood pressure, diastolic blood pressure, age, and congestive heart failure with p-values 0.018, 0.019, 0.017, 0.033, and 0.022, respectively). Conclusion: NLR predicted the worsening of the renal function in diabetic patients. Further studies are needed to confirm this result.

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Pathogenic perspectives for the role of inflammation in diabetic nephropathy

Cited by 169 publications

References 176 publications

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

Neutrophil-to-Lymphocyte Ratio as a Predictor of Worsening Renal Function in Diabetic Patients (3-Year Follow-Up Study)

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