目的:观察烟酰胺(Nam)对糖尿病肾病(DKD)小鼠的影响并探讨其作用机制。
方法:30只DBA/2J小鼠随机分为三组。链脲佐菌素(STZ)诱导高血糖8周后,对STZ+Nam和STZ+NS小鼠给予Nam和生理盐水,分别,八个星期。非糖尿病小鼠(NDM)作为对照组。将20只In2-/-秋田小鼠随机分为两组。高血糖8周后,对Akita+Nam和Akita+NS小鼠给予Nam和生理盐水,分别,6周。野生型同窝作为对照组。分析肾损伤的标志物,并探讨了人近端肾小管HK2细胞的分子机制。
结果:STZ+Nam和Akita+Nam组的尿白蛋白-肌酐比值(UACR)和肾损伤分子1(KIM-1)降低。病理分析显示Nam改善了肾小球基底膜的结构,改善的肾小球硬化,减少了细胞外基质和胶原的积累。与糖尿病对照组相比,肾纤维化,炎症,在Nam处理的小鼠中,氧化应激降低。高糖抑制了人近端肾小管HK2细胞中沉默调节蛋白1(Sirt1)的表达,而Nam处理增强了其表达。然而,在具有Sirt1敲低的HK2细胞中,Nam的保护作用被废除了,表明Nam的有益作用部分依赖于Sirt1。
结论:Nam对高血糖引起的肾损伤具有肾脏保护作用,可能是治疗DKD的潜在靶点。
OBJECTIVE: To investigate the effect of nicotinamide (Nam) on diabetic kidney disease (DKD) in mice and explore its mechanism.
METHODS: Thirty DBA/2 J mice were randomly assigned to three groups. After 8 weeks of hyperglycemia induced by streptozocin (STZ), Nam and saline were administrated to STZ + Nam and STZ + NS mice, respectively, for 8 weeks. Non-diabetic mice (NDM) were used as control group. Twenty In2-/- Akita mice were randomly divided into two groups. After 8 weeks of hyperglycemia, Nam and saline were administered to Akita + Nam and Akita + NS mice, respectively, for 6 weeks. Wild-type littermates were used as control group. Markers of renal injury were analyzed, and the molecular mechanisms were explored in human proximal tubular HK2 cells.
RESULTS: Urinary albumin-to-creatinine ratio (UACR) and kidney injury molecule 1 (KIM-1) decreased in the STZ + Nam and Akita + Nam groups. Pathological analysis showed that Nam improved the structure of glomerular basement membrane, ameliorated glomerular sclerosis, and decreased the accumulation of extracellular matrix and collagen. Compared to the diabetic control group, renal fibrosis, inflammation, and oxidative stress were reduced in the Nam-treated mice. The expression of sirtuin 1 (Sirt1) in human proximal tubular HK2 cells was inhibited by high glucose and Nam treatment enhanced its expression. However, in HK2 cells with Sirt1 knockdown, the protective effect of Nam was abolished, indicating that the beneficial effect of Nam was partially dependent on Sirt1.
CONCLUSIONS: Nam has a renoprotective effect against renal injury caused by hyperglycemia and may be a potential target for the treatment of DKD.