Extracellular signal-regulated kinase 1/2 regulates NAD metabolism during acute kidney injury through microRNA-34a-media
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Extracellular signal‑regulated kinase 1/2 regulates NAD metabolism during acute kidney injury through microRNA‑34a‑mediated NAMPT expression Justin B. Collier1,2,3 · Rick G. Schnellmann3,4,5 Received: 4 January 2019 / Revised: 26 October 2019 / Accepted: 20 November 2019 © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019
Abstract Prior studies have established the important role of extracellular signal-regulated kinase 1/2 (ERK1/2) as a mediator of acute kidney injury (AKI). We demonstrated rapid ERK1/2 activation induced renal dysfunction following ischemia/reperfusion (IR)-induced AKI and downregulated the mitochondrial biogenesis (MB) regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in mice. In this study, ERK1/2 regulation of cellular nicotinamide adenine dinucleotide (NAD) and PGC-1α were explored. Inhibition of ERK1/2 activation during AKI in mice using the MEK1/2 inhibitor, trametinib, attenuated renal cortical oxidized NAD ( NAD+) depletion. The rate-limiting NAD biosynthesis salvage enzyme, NAMPT, decreased following AKI, and this decrease was prevented by ERK1/2 inhibition. The microRNA miR34a decreased with the inhibition of ERK1/2, leading to increased NAMPT protein. Mice treated with a miR34a mimic prevented increases in NAMPT protein in the renal cortex in the presence of ERK1/2 inhibition. In addition, ERK1/2 activation increased acetylated PGC-1α, the less active form, whereas inhibition of ERK1/2 activation prevented an increase in acetylated PGC-1α after AKI through SIRT1 and N AD+ attenuation. These results implicate IR-induced ERK1/2 activation as an important contributor to the downregulation of both PGC-1α and N AD+ pathways that ultimately decrease cellular metabolism and renal function. Inhibition of ERK1/2 activation prior to the initiation of IR injury attenuated decreases in PGC-1α and NAD+ and prevented kidney dysfunction. Keywords ERK1/2 · Nicotinamide adenine dinucleotide · Kidney · Mitochondrial biogenesis · Cellular metabolism · Ischemia–reperfusion · miR-34a
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03391-z) contains supplementary material, which is available to authorized users. * Justin B. Collier [email protected] Rick G. Schnellmann [email protected] 1
Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
2
Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
3
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA
4
Southern Arizona VA Health Care System, Tucson, AZ, USA
5
Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ, USA
Introduction Extracellular regulated kinas
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