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

doi:10.1016/j.celrep.2019.03.024

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

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	199-212.e5
Journal	Cell Reports
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2019.03.024
Publication status	Published - 2019 Apr 2

Keywords

NAD
NMN
Nampt
Sirt6
TBM thickening
diabetic nephropathy
metabo-fibrosis

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2019.03.024

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@article{a93be707c6f4482d87d23f0835fc521a,

title = "Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy",

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. ",

keywords = "NAD, NMN, Nampt, Sirt6, TBM thickening, diabetic nephropathy, metabo-fibrosis",

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

note = "Funding Information: The authors wish to thank P. Mundel and K. Asanuma for providing cultured podocytes and J. Yoshino for providing Nampt flox/flox mice. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant no. 22790800 ). Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = apr,

day = "2",

doi = "10.1016/j.celrep.2019.03.024",

language = "English",

volume = "27",

pages = "199--212.e5",

journal = "Cell Reports",

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number = "1",

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TY - JOUR

T1 - Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy

AU - Muraoka, Hirokazu

AU - Hasegawa, Kazuhiro

AU - Sakamaki, Yusuke

AU - Minakuchi, Hitoshi

AU - Kawaguchi, Takahisa

AU - Yasuda, Itaru

AU - Kanda, Takeshi

AU - Tokuyama, Hirobumi

AU - Wakino, Shu

AU - Itoh, Hiroshi

N1 - Funding Information: The authors wish to thank P. Mundel and K. Asanuma for providing cultured podocytes and J. Yoshino for providing Nampt flox/flox mice. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant no. 22790800 ). Publisher Copyright: © 2019 The Author(s)

PY - 2019/4/2

Y1 - 2019/4/2

N2 - 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.

AB - 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.

KW - NAD

KW - NMN

KW - Nampt

KW - Sirt6

KW - TBM thickening

KW - diabetic nephropathy

KW - metabo-fibrosis

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U2 - 10.1016/j.celrep.2019.03.024

DO - 10.1016/j.celrep.2019.03.024

M3 - Article

C2 - 30943401

AN - SCOPUS:85063419012

SN - 2211-1247

VL - 27

SP - 199-212.e5

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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