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  • Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury.

Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury.

Physiological genomics (2012-12-20)
Chun Cheng Andy Chen, Aron M Geurts, Howard J Jacob, Fan Fan, Richard J Roman
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
CompoZr Custom Zinc Finger Nuclease (ZFN), ZFN plasmid only
Sigma-Aldrich
CompoZr® Custom Zinc Finger Nuclease (ZFN), ZFN plasmid and mRNA