Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy

被引：71
作者：
Muraoka, Hirokazu [1 ]
Hasegawa, Kazuhiro [1 ]
Sakamaki, Yusuke [2 ]
Minakuchi, Hitoshi [1 ]
Kawaguchi, Takahisa [1 ]
Yasuda, Itaru [1 ]
Kanda, Takeshi [1 ]
Tokuyama, Hirobumi [1 ]
Wakino, Shu [1 ]
Itoh, Hiroshi [1 ]
机构：
[1] Keio Univ, Sch Med, Dept Internal Med, Tokyo 1608582, Japan
[2] Ichikawa Gen Hosp, Dept Internal Med, Tokyo Dent Coll, Chiba 2728583, Japan
来源：
CELL REPORTS | 2019年 / 27卷 / 01期
关键词：
DEPENDENT GENE-EXPRESSION; TISSUE INHIBITOR; SIRT1; PROTECTS; CELL-SURVIVAL; APOPTOSIS; ALBUMINURIA; NAD(+); METALLOPROTEINASES; OVEREXPRESSION; DEACETYLATION;
D O I：
10.1016/j.celrep.2019.03.024
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Nicotinamide adenine dinucleotide (NAD(+)) metabolism plays a critical role in kidneys. We previously reported that decreased secretion of a NAD(+) precursor, nicotinamide mononucleotide (NMN), from proximal tubules (PTs) can trigger diabetic albuminuria. In the present study, we investigated the role of NMN-producing enzyme nicotinamide phosphoribosyl-transferase (Nampt) in diabetic nephropathy. The expression of Nampt in PTs was downregulated in streptozotocin (STZ)-treated diabetic mice when they exhibited albuminuria. This albuminuria was ameliorated in PT-specific Nampt-overexpressing transgenic (TG) mice. PT-specific Nampt-conditional knockout (Nampt CKO) mice exhibited TBM thickening and collagen deposition, which were associated with the upregulation of the profibrogenic gene TIMP-1. Nampt CKO mice also exhibited the downregulation of sirtuins, particularly in Sirt6. PT-specific Sirt6-knockout mice exhibited enhanced fibrotic phenotype resembling that of Nampt CKO mice with increased Timp1 expression. In conclusion, the Nampt-Sirt6 axis in PTs serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.
引用
收藏
页码：199 / +
页数：19
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