Evaluation of inducible nitric oxide synthase inhibition on kidney function and structure in high-fat diet-induced kidney disease

Blanche Martin, Nathalie Caron, Inès Jadot, Vanessa Colombaro, Gabrielle Federici, Clara Depommier, Anne Émilie Declèves

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New Findings: What is the central question of this study? The metabolic pathways regulating the effects of obesity on the kidney remain unknown. We sought to determine whether inducible nitric oxide synthase (iNOS) is involved in the underlying mechanisms of high-fat diet-induced kidney disease using a specific iNOS inhibitor, N6-(1-iminoethyl)-l-lysine hydrochloride (L-NIL). What is the main finding and its importance? We did not demonstrate an upregulation of iNOS renal expression after high caloric intake, suggesting that iNOS might not be a crucial player in the development of obesity-induced kidney disease. Although L-NIL treatment clearly ameliorated systemic metabolic parameters, the effect on loss of renal function, impairment of tubular integrity, oxidative stress and inflammation appeared to be more moderate. Central obesity is related to caloric excess, promoting deleterious cellular responses in targeted organs. Nitric oxide (NO) has been determined as a key player in the pathogenesis of metabolic diseases. Here, we investigated the implication of inducible NO synthase (iNOS) in the development of obesity-induced kidney disease. C57Bl/6 male mice were randomized to a low-fat diet (LFD) or a high-fat diet (HFD) and treated with N6-(1-iminoethyl)-l-lysine hydrochloride (L-NIL), a specific iNOS inhibitor, for 16 weeks. Mice fed an HFD exhibited a significant increase in body weight, fasting blood glucose and plasma concentrations of non-esterified fatty acids, triglyceride and insulin. Inhibition of iNOS prevented these changes in mice fed an HFD. Interestingly, the significant increase in albuminuria and mesangial matrix expansion were not ameliorated with L-NIL, whereas a significant decrease in proteinuria, N-acetyl-β-d-glucosaminidase excretion and renal triglyceride content were found, suggesting that iNOS inhibition is more suitable for tubular function than glomerular function. The urinary concentration of hydrogen peroxide, a stable product of reactive oxygen species production, that was found to be increased in mice fed an HFD, was significantly reduced with L-NIL. Finally, despite a moderate effect of L-NIL on inflammatory processes in the kidney, we demonstrated a positive impact of this treatment on adipocyte hypertrophy and on adipose tissue inflammation. These results suggest that inhibition of iNOS leads to a moderate beneficial effect on kidney function in mice fed an HFD. Further studies are needed for better understanding of the role of iNOS in obesity-induced kidney disease.

Original languageEnglish
Pages (from-to)125-140
Number of pages16
JournalExperimental Physiology
Issue number1
Publication statusPublished - 1 Jan 2018


  • chronic kidney disease
  • nitric oxide
  • obesity


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