Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease.
Impaired Nicotinamide Adenine Dinucleotide Biosynthesis in the Kidney of Chronic Kidney Disease.
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DOI：
10.3389/fphys.2021.723690
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发表时间：
2021
影响因子：
4
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Liu X;Luo D;Huang S;Liu S;Zhang B;Wang F;Lu J;Chen J;Li S
慢性肾脏疾病（CKD）是一个全球性的公共卫生问题，具有很高的发病率和死亡率。烟酰胺腺嘌呤二核苷酸（NAD+）水平的降低与衰老、癌症、神经退行性疾病和代谢紊乱有关。然而，CKD中肾脏NAD+水平和生物合成途径的改变尚不清楚。在本研究中，我们旨在评估肾脏NAD+水平，并检测两种不同类型CKD大鼠模型中NAD+三种生物合成途径中关键酶的表达。分别采用5/6肾切除术（5/6 Nx）和含腺嘌呤饲料建立CKD大鼠模型。采用血清肌酐（Scr）和尿素氮（BUN）测定肾功能。肾病理采用周期性酸-希夫（PAS）和马松三色染色。Western blot检测NAD+ 3条生物合成途径中关键酶的表达。结果显示，Scr和BUN水平升高，中性粒细胞明胶酶相关脂钙蛋白（NGAL）上调，肾小球肥大，肾纤维化，CKD大鼠模型成功建立。两种CKD模型大鼠肾脏NAD+和NADH含量均下降，且NAD+水平与CKD大鼠Scr和BUN水平呈负相关。参与NAD+生物合成的三种关键酶在两种CKD模型的肾脏中均显著下调。它们分别是新生途径中的喹啉酸磷酸核糖基转移酶（QPRT）、修复途径中的烟酰胺单核苷酸腺苷转移酶1 （NMNAT1）和NMNAT3。此外，CKD大鼠NAD+消耗酶sirtuin 3 （SIRT3）和CD38的表达显著降低。综上所述，NAD+的生物合成在CKD中明显受损，这可能与QPRT和NMNAT 1/3的下调有关。
Chronic kidney disease (CKD) is a global public health problem with high morbidity and mortality. Decreased nicotinamide adenine dinucleotide (NAD+) levels were found to be associated with aging, cancer, and neurodegenerative and metabolic disorders. However, the alteration of renal NAD+ levels and biosynthesis pathways in CKD is less known. In the present study, we aimed to evaluate renal NAD+ levels and tested the expression of key enzymes in three NAD+ biosynthesis pathways in two different types of CKD rat model. CKD rat models were established by 5/6 nephrectomy (5/6 Nx) and feeding with adenine-containing feed, respectively. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathology was evaluated by periodic acid-Schiff (PAS) and Masson’s trichrome staining. The expression of key enzymes in three NAD+ biosynthesis pathways was determined and quantified by Western blot analysis. The results showed CKD rat models were successfully established as evidenced by increased Scr and BUN levels, upregulation of neutrophil gelatinase-associated lipocalin (NGAL), glomerular hypertrophy, and renal fibrosis. Renal NAD+ and NADH content were both declined in two CKD rat models, and NAD+ levels were negatively correlated with Scr and BUN levels in CKD rats. Three key enzymes involved in NAD+ biosynthesis were significantly downregulated in the kidney of both of the two CKD models. They were quinolinate phosphoribosyltransferase (QPRT) in the de novo pathway, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), and NMNAT3 in the salvage pathway. Moreover, the expression of NAD+-consuming enzymes sirtuin 3 (SIRT3) and CD38 decreased significantly in CKD rats. In conclusion, NAD+ biosynthesis was significantly impaired in CKD, which may attribute to downregulation of QPRT and NMNAT 1/3.
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影响因子：
4.2
作者：
Kumakura S;Sato E;Sekimoto A;Hashizume Y;Yamakage S;Miyazaki M;Ito S;Harigae H;Takahashi N
通讯作者：
Takahashi N
DOI：
10.1038/s41580-020-00313-x
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Covarrubias AJ;Perrone R;Grozio A;Verdin E
通讯作者：
Verdin E
影响因子：
8.1
作者：
Amjad S;Nisar S;Bhat AA;Shah AR;Frenneaux MP;Fakhro K;Haris M;Reddy R;Patay Z;Baur J;Bagga P
通讯作者：
Bagga P
靶向Sirtuin 1以改善新陈代谢：您所需要的是NAD（+）？
影响因子：
21.1
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J
影响因子：
4.8
作者：
Zhang, XJ;Kurnasov, OV;Zhang, H
通讯作者：
Zhang, H