Inorganic nitrate and nitrite ameliorate kidney fibrosis by restoring lipid metabolism via dual regulation of AMP-activated protein kinase and the AKT-PGC1α pathway.

Autor:	Li X; Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Zhuge Z; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Carvalho LRRA; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Braga VA; Department of Biotechnology, Federal University of Paraíba, João Pessoa, PB, Brazil., Lucena RB; Department of Veterinary Sciences, Federal University of Paraíba, Areia, PB, Brazil., Li S; Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Schiffer TA; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Han H; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Weitzberg E; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden., Lundberg JO; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Carlström M; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: mattias.carlstrom@ki.se.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2022 May; Vol. 51, pp. 102266. Date of Electronic Publication: 2022 Feb 17.
DOI:	10.1016/j.redox.2022.102266
Abstrakt:	Background: Renal fibrosis, associated with oxidative stress and nitric oxide (NO) deficiency, contributes to the development of chronic kidney disease and renal failure. As major energy source in maintaining renal physiological functions, tubular epithelial cells with decreased fatty acid oxidation play a key role in renal fibrosis development. Inorganic nitrate, found in high levels in certain vegetables, can increase the formation and signaling by bioactive nitrogen species, including NO, and dampen oxidative stress. In this study, we evaluated the therapeutic value of inorganic nitrate treatment on development of kidney fibrosis and investigated underlying mechanisms including regulation of lipid metabolism in tubular epithelial cells. Methods: Inorganic nitrate was supplemented in a mouse model of complete unilateral ureteral obstruction (UUO)-induced fibrosis. Inorganic nitrite was applied in transforming growth factor β-induced pro-fibrotic cells in vitro. Metformin was administrated as a positive control. Fibrosis, oxidative stress and lipid metabolism were evaluated. Results: Nitrate treatment boosted the nitrate-nitrite-NO pathway, which ameliorated UUO-induced renal dysfunction and fibrosis in mice, represented by improved glomerular filtration and morphological structure and decreased renal collagen deposition, pro-fibrotic marker expression, and inflammation. In human proximal tubule epithelial cells (HK-2), inorganic nitrite treatment prevented transforming growth factor β-induced pro-fibrotic changes. Mechanistically, boosting the nitrate-nitrite-NO pathway promoted AMP-activated protein kinase (AMPK) phosphorylation, improved AKT-mediated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) activity and restored mitochondrial function. Accordingly, treatment with nitrate (in vivo) or nitrite (in vitro) decreased lipid accumulation, which was associated with dampened NADPH oxidase activity and mitochondria-derived oxidative stress. Conclusions: Our findings indicate that inorganic nitrate and nitrite treatment attenuates the development of kidney fibrosis by targeting oxidative stress and lipid metabolism. Underlying mechanisms include modulation of AMPK and AKT-PGC1α pathways. (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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