title: Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury.
abstract: The present study employed a zinc-finger nuclease strategy to create heterozygous knockout (KO) rats for the transforming growth factor-β1 (Tgfb1) gene on the Dahl SS/Jr genetic background (TGF-β1(+/-) Dahl S). Intercrossing TGF-β1(+/-) rats did not produce any homozygous KO rats (66.4% +/-, 33.6% +/+), indicating that the mutation is embryonic lethal. Six-week-old wild-type (WT) littermates and TGF-β1(+/-) Dahl S rats were fed a 0.4% (low salt, LS) or 8% NaCl (high salt, HS) diet for 5 wk. Renal cortical expression of TGF-β1, urinary TGF-β1 excretion, proteinuria, glomerular injury and tubulointerstitial fibrosis, and systolic blood pressure were similar in WT and TGF-β1(+/-) Dahl S rats maintained on the LS diet. The expression and urinary excretion of TGF-β1 increased to a greater extent in WT than in TGF-β1(+/-)Dahl S rats fed an HS diet for 1 wk. Systolic blood pressure rose by the same extent to 235 ± 2 mmHg in WT and 239 ± 4 mmHg in TGF-β1(+/-) Dahl S rats fed a HS diet for 5 wk. However, urinary protein excretion was significantly lower in TGF-β1(+/-) Dahl S than in the WT animals. The degree of glomerular injury and renal cortical and outer medullary fibrosis was markedly less in TGF-β1(+/-) than in WT rats. These findings suggest that the loss of one copy of the TGF-β1 gene blunts the increase in renal TGF-β1 protein expression and slows the progression of proteinuria, glomerulosclerosis, and renal interstitial fibrosis in Dahl S rats fed an HS diet independently of changes in blood pressure.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi 39211, USA.
authors.forename: Chun Cheng Andy
authors.initials: CC
authors.lastname: Chen
authors.forename: Aron M
authors.initials: AM
authors.lastname: Geurts
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000818:Animals; D001483:Base Sequence; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006973:Hypertension / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007668:Kidney / Q000502:physiology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D011507:Proteinuria / Q000235:genetics; D051381:Rats; D020303:Rats, Inbred Dahl; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000235:genetics; D053782:Transforming Growth Factor beta3 / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; C113267:nephrin