title: Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney.
abstract: The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Luke M
authors.initials: LM
authors.lastname: Shelton
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
authors.forename: Adam
authors.initials: A
authors.lastname: Lister
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Walsh
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Rosalind E
authors.initials: RE
authors.lastname: Jenkins
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.|Department of Chemistry, School of Physical Sciences, University of Liverpool, Liverpool, UK.
authors.forename: Michael H L
authors.initials: MH
authors.lastname: Wong
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.|CN Bio Innovations Ltd, Centre for Innovation & Enterprise, Oxford University Begbroke Science Park, Oxford, UK.
authors.forename: Cliff
authors.initials: C
authors.lastname: Rowe
authors.affiliation: School of Veterinary Science, University of Liverpool, Liverpool, UK.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Ricci
authors.affiliation: School of Veterinary Science, University of Liverpool, Liverpool, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Ressel
authors.affiliation: Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Demougin
authors.affiliation: Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, Switzerland.
authors.forename: Vanja
authors.initials: V
authors.lastname: Vukojevic
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.|Department of Chemistry, School of Physical Sciences, University of Liverpool, Liverpool, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Goldring
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Kitteringham
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Copple