Martin Blanche, Caron Nathalie, Jadot Inès, Colombaro Vanessa, Federici Gabrielle, Depommier Clara, Declèves Anne-Émilie
Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), Namur, Belgium.
Laboratory of Molecular Biology, University of Mons (UMONS), Mons, Belgium.
Exp Physiol. 2018 Jan 1;103(1):125-140. doi: 10.1113/EP086594. Epub 2017 Nov 22.
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.
本研究的核心问题是什么？调节肥胖对肾脏影响的代谢途径仍不清楚。我们试图使用特异性诱导型一氧化氮合酶（iNOS）抑制剂N6-（1-亚氨基乙基）-L-赖氨酸盐酸盐（L-NIL）来确定iNOS是否参与高脂饮食诱导的肾脏疾病的潜在机制。主要发现及其重要性是什么？我们并未证明高热量摄入后iNOS在肾脏中的表达上调，这表明iNOS可能不是肥胖诱导的肾脏疾病发展中的关键因素。尽管L-NIL治疗明显改善了全身代谢参数，但对肾功能丧失、肾小管完整性受损、氧化应激和炎症的影响似乎较为温和。中心性肥胖与热量过剩有关，会在靶器官中引发有害的细胞反应。一氧化氮（NO）已被确定为代谢疾病发病机制中的关键因素。在此，我们研究了诱导型NO合酶（iNOS）在肥胖诱导的肾脏疾病发展中的作用。将C57Bl/6雄性小鼠随机分为低脂饮食（LFD）组或高脂饮食（HFD）组，并用特异性iNOS抑制剂N6-（1-亚氨基乙基）-L-赖氨酸盐酸盐（L-NIL）治疗16周。喂食HFD的小鼠体重、空腹血糖以及非酯化脂肪酸、甘油三酯和胰岛素的血浆浓度显著增加。抑制iNOS可防止喂食HFD的小鼠出现这些变化。有趣的是，L-NIL并未改善蛋白尿和系膜基质扩张的显著增加，然而却发现蛋白尿、N-乙酰-β-D-氨基葡萄糖苷酶排泄和肾脏甘油三酯含量显著降低，这表明抑制iNOS对肾小管功能的适用性优于肾小球功能。喂食HFD的小鼠中发现的活性氧产生的稳定产物过氧化氢的尿浓度升高，L-NIL可使其显著降低。最后，尽管L-NIL对肾脏炎症过程的影响较为温和，但我们证明了这种治疗对脂肪细胞肥大和脂肪组织炎症有积极影响。这些结果表明，抑制iNOS对喂食HFD的小鼠的肾功能有适度的有益作用。需要进一步研究以更好地了解iNOS在肥胖诱导的肾脏疾病中的作用。
