Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy
Summary: 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 t...
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doaj-0e45b2ac4f6840a3896d5ac3246635e72020-11-24T22:26:10ZengElsevierCell Reports2211-12472019-04-01271199212.e5Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic NephropathyHirokazu Muraoka0Kazuhiro Hasegawa1Yusuke Sakamaki2Hitoshi Minakuchi3Takahisa Kawaguchi4Itaru Yasuda5Takeshi Kanda6Hirobumi Tokuyama7Shu Wakino8Hiroshi Itoh9Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba 272-8583, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan; Corresponding authorDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, JapanSummary: 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, Nampt, Sirt6, metabo-fibrosis, NMN, TBM thickening, diabetic nephropathyhttp://www.sciencedirect.com/science/article/pii/S2211124719303407 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hirokazu Muraoka Kazuhiro Hasegawa Yusuke Sakamaki Hitoshi Minakuchi Takahisa Kawaguchi Itaru Yasuda Takeshi Kanda Hirobumi Tokuyama Shu Wakino Hiroshi Itoh |
spellingShingle |
Hirokazu Muraoka Kazuhiro Hasegawa Yusuke Sakamaki Hitoshi Minakuchi Takahisa Kawaguchi Itaru Yasuda Takeshi Kanda Hirobumi Tokuyama Shu Wakino Hiroshi Itoh Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy Cell Reports |
author_facet |
Hirokazu Muraoka Kazuhiro Hasegawa Yusuke Sakamaki Hitoshi Minakuchi Takahisa Kawaguchi Itaru Yasuda Takeshi Kanda Hirobumi Tokuyama Shu Wakino Hiroshi Itoh |
author_sort |
Hirokazu Muraoka |
title |
Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy |
title_short |
Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy |
title_full |
Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy |
title_fullStr |
Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy |
title_full_unstemmed |
Role of Nampt-Sirt6 Axis in Renal Proximal Tubules in Extracellular Matrix Deposition in Diabetic Nephropathy |
title_sort |
role of nampt-sirt6 axis in renal proximal tubules in extracellular matrix deposition in diabetic nephropathy |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-04-01 |
description |
Summary: 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, Nampt, Sirt6, metabo-fibrosis, NMN, TBM thickening, diabetic nephropathy |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719303407 |
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