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

Hirokazu Muraoka, Kazuhiro Hasegawa, Yusuke Sakamaki, Hitoshi Minakuchi, Takahisa Kawaguchi, Itaru Yasuda, Takeshi Kanda, Hirobumi Tokuyama, Shu Wakino, Hiroshi Itoh

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Abstract

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 phosphoribosyltransferase (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. Muraoka et al. reveal that the Nampt-Sirt6 axis in proximal tubules serves as a key player in fibrogenic extracellular matrix remodeling in diabetic nephropathy.

Original languageEnglish
Pages (from-to)199-212.e5
JournalCell Reports
Volume27
Issue number1
DOIs
Publication statusPublished - 2019 Apr 2

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Keywords

  • diabetic nephropathy
  • metabo-fibrosis
  • NAD
  • Nampt
  • NMN
  • Sirt6
  • TBM thickening

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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