Journal
CELL REPORTS
Volume 27, Issue 1, Pages 199-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.03.024
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Funding
- Scientific Research Fund of the Ministry of Education, Culture, Sports, Science, and Technology of Japan [22790800]
- Grants-in-Aid for Scientific Research [22790800] Funding Source: KAKEN
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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.
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