1-Methylnicotinamide ameliorates lipotoxicity-induced oxidative stress and cell death in kidney proximal tubular cells.
Free fatty acid-bound albumin (FFA-albumin)-related oxidative stress is involved in the pathogenesis of proximal tubular cell (PTC) damage and subsequent renal dysfunction in patients with refractory proteinuria. Nicotinamide adenine dinucleotide (NAD) metabolism has recently been focused on as a novel therapeutic target for several modern diseases, including diabetes. This study was designed to identify a novel molecule in NAD metabolism to protect PTCs from lipotoxicity-related oxidative stress. Among 19 candidate enzymes involved in mammalian NAD metabolism, the mRNA expression level of nicotinamide n-methyltransferase (NNMT) was significantly increased in both the kidneys of FFA-albumin-overloaded mice and cultured PTCs stimulated with palmitate-albumin. Knockdown of NNMT exacerbated palmitate-albumin-induced cell death in cultured PTCs, whereas overexpression of NNMT inhibited it. Intracellular concentration of 1-Methylnicotinamide (1-MNA), a metabolite of NNMT, increased and decreased in cultured NNMT-overexpressing and -knockdown PTCs, respectively. Treatment with 1-MNA inhibited palmitate-albumin-induced mitochondrial reactive oxygen species generation and cell death in cultured PTCs. Furthermore, oral administration of 1-MNA ameliorated oxidative stress, apoptosis, necrosis, inflammation, and fibrosis in the kidneys of FFA-albumin-overloaded mice. In conclusion, NNMT-derived 1-MNA can reduce lipotoxicity-mediated oxidative stress and cell damage in PTCs. Supplementation of 1-MNA may have potential as a new therapy in patients with refractory proteinuria.
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Yuki
Y
Tanaka
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. Electronic address: skume@belle.shiga-med.ac.jp.
Shinji
S
Kume
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Hisazumi
H
Araki
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Jun
J
Nakazawa
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Masami
M
Chin-Kanasaki
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Shin-ichi
S
Araki
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan; Osaka Laboratory, CMIC Pharma Science Co., Ltd., Suita, Osaka, Japan.
Fumiyuki
F
Nakagawa
Department of Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa, Japan.
Daisuke
D
Koya
Division of Metabolism and Biosystemic Science, Asahikawa Medical University, Asahikawa, Hokka ido, Japan.
Masakazu
M
Haneda
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Hiroshi
H
Maegawa
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Takashi
T
Uzu
D000418:Albumins / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000633:toxicity; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011507:Proteinuria / Q000150:complications*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
D000418:Albumins; D005230:Fatty Acids, Nonesterified; D034741:RNA, Small Interfering; D009536:Niacinamide; D050903:Nicotinamide N-Methyltransferase; C024058:N(1)-methylnicotinamide
Apoptosis; Lipotoxicity; Necrosis; Nicotinamide N-methyltransferase (NNMT); Nicotinamide adenine dinucleotide (NAD); Proteinuria; Proximal tubular cell damage