title: Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a mouse model of diabetes.
abstract: OBJECTIVE
  We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes.
  
  
  METHODS
  Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied.
  
  
  RESULTS
  Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1-7 receptor [MasR]) expression, and normalised urinary Ang 1-7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-β1 and Tgf-βrII gene expression. Furthermore, hnRNP F overexpression prevented TGF-β1 signalling and TGF-β1 inhibition of Ace-2 gene expression.
  
  
  CONCLUSIONS
  These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes.
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada.
authors.forename: Chao-Sheng
authors.initials: CS
authors.lastname: Lo
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada.
authors.forename: Shiao-Ying
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada.
authors.forename: Shaaban
authors.initials: S
authors.lastname: Abdo
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chenier
authors.affiliation: Research Centre, Maisonneuve-Rosemont Hospital, Université de Montréal, Montreal, QC, Canada.
authors.forename: Janos G
authors.initials: JG
authors.lastname: Filep
authors.affiliation: Pediatric Nephrology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada. shao.ling.zhang@umontreal.ca.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Centre de recherche, Centre hospitalier de l'Université de Montréal (CRCHUM) - Tour Viger Pavillon R, Université de Montréal, 900 Saint-Denis Street, Montreal, QC, H2X 0A9, Canada. john.chan@umontreal.ca.
authors.forename: John S D
authors.initials: JS
authors.lastname: Chan
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D053773:Transforming Growth Factor beta1; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2
keywords: ACE-2; Akita mice; Angiotensinogen; Diabetes; Heterogeneous nuclear ribonucleoprotein F; Hypertension; Renal fibrosis; TGF-β1