Heterozygous knockout of transforming growth factor-β1 protects dahl s rats against high salt-induced renal injury

Richard J. Roman, Chun Cheng Andy Chen, Aron M. Geurts, Howard J. Jacob, Fan Fan

Research output: Contribution to journalArticlepeer-review

Abstract

Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury. Physiol Genomics 45: 110-118, 2013. First published December 18, 2012; doi:10.1152/physiolgenomics.00119.2012.-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.

Original languageEnglish (US)
Pages (from-to)110-118
Number of pages9
JournalPhysiological Genomics
Volume45
Issue number3
DOIs
StatePublished - Feb 4 2013
Externally publishedYes

Keywords

  • Glomerular injury
  • Hypertension
  • Kidney disease
  • Renal fibrosis
  • Transforming growth factor beta 1

ASJC Scopus subject areas

  • Physiology
  • Genetics

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