title: Delayed treatment with fenofibrate protects against high-fat diet-induced kidney injury in mice: the possible role of AMPK autophagy.
abstract: Fenofibrate activates not only peroxisome proliferator-activated receptor-α (PPARα) but also adenosine monophosphate-activated protein kinase (AMPK). AMPK-mediated cellular responses protect kidney from high-fat diet (HFD)-induced injury, and autophagy resulting from AMPK activation has been regarded as a stress-response mechanism. Thus the present study examined the role of AMPK and autophagy in the renotherapeutic effects of fenofibrate. C57BL/6J mice were divided into three groups: normal diet (ND), HFD, and HFD + fenofibrate (HFD + FF). Fenofibrate was administered 4 wk after the initiation of the HFD when renal injury was initiated. Mouse proximal tubule cells (mProx24) were used to clarify the role of AMPK. Feeding mice with HFD for 12 wk induced insulin resistance and kidney injury such as albuminuria, glomerulosclerosis, tubular injury, and inflammation, which were effectively inhibited by fenofibrate. In addition, fenofibrate treatment resulted in the activation of renal AMPK, upregulation of fatty acid oxidation (FAO) enzymes and antioxidants, and induction of autophagy in the HFD mice. In mProx24 cells, fenofibrate activated AMPK in a concentration-dependent manner, upregulated FAO enzymes and antioxidants, and induced autophagy, all of which were inhibited by treatment of compound C, an AMPK inhibitor. Fenofibrate-induced autophagy was also significantly blocked by AMPKα1 siRNA but not by PPARα siRNA. Collectively, these results demonstrate that delayed treatment with fenofibrate has a therapeutic effect on HFD-induced kidney injury, at least in part, through the activation of AMPK and induction of subsequent downstream effectors: autophagy, FAO enzymes, and antioxidants.
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Minji
authors.initials: M
authors.lastname: Sohn
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Keumji
authors.initials: K
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Md Jamal
authors.identifier: http://orcid.org/0000-0003-2911-3255
authors.initials: MJ
authors.lastname: Uddin
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Gayoung
authors.initials: G
authors.lastname: Lee
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Inah
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Hyeji
authors.initials: H
authors.lastname: Kang
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Hyunji
authors.initials: H
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea hha@ewha.ac.kr.
authors.forename: Hunjoo
authors.identifier: http://orcid.org/0000-0002-5601-1265
authors.initials: H
authors.lastname: Ha
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000419:Albuminuria / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000960:Hypolipidemic Agents; D020011:Protective Agents; D055372:AMP-Activated Protein Kinases; D011345:Fenofibrate
keywords: AMPK; autophagy; fenofibrate; high-fat diet; kidney injury