title: Catalase overexpression prevents nuclear factor erythroid 2-related factor 2 stimulation of renal angiotensinogen gene expression, hypertension, and kidney injury in diabetic mice.
abstract: This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2-related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-κB and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice.
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Shaaban
authors.initials: S
authors.lastname: Abdo
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Abouzar
authors.initials: A
authors.lastname: Otoukesh
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Anindya
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Chao-Sheng
authors.initials: CS
authors.lastname: Lo
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chenier
authors.affiliation: Research Centre, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Janos G
authors.initials: JG
authors.lastname: Filep
authors.affiliation: Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Shao Ling
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada john.chan@umontreal.ca.
authors.forename: John S D
authors.initials: JS
authors.lastname: Chan
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013871:Thiones; D013876:Thiophenes
chemical_list: D001786:Blood Glucose; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D011719:Pyrazines; D018894:Reverse Transcriptase Inhibitors; D013871:Thiones; D013876:Thiophenes; D000808:Angiotensinogen; C026209:oltipraz; D002374:Catalase