Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

Karl A. Nath, Anthony J. Croatt, Gina M. Warner, Joseph P. Grande

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

TGF-(β1 contributes to chronic kidney disease, at least in part, via Smad3. TGF-(β1 is induced in the kidney following acute ischemia, and there is increasing evidence that TGF-(β1 may protect against acute kidney injury. As there is a paucity of information regarding the functional significance of Smad3 in acute kidney injury, the present study explored this issue in a murine model of ischemic acute kidney injury in Smad3+/+ and Smad3-/-mice. We demonstrate that, at 24 h after ischemia, Smad3 is significantly induced in Smad3+/+ mice, whereas Smad3-/- mice fail to express this protein in the kidney in either the sham or postischemic groups. Compared with Smad3+/+ mice, and 24 h following ischemia, Smad3-/-mice exhibited greater preservation of renal function as measured by blood urea nitrogen (BUN) and serum creatinine; less histological injury assessed by both semiquantitative and qualitative analyses; markedly suppressed renal expression of IL-6 and endothelin-1 mRNA (but comparable expression of MCP-1, TNF-a, and heme oxygenase-1 mRNA); and no increase in plasma IL-6 levels, the latter increasing approximately sixfold in postischemic Smad3+/+ mice. We conclude that genetic deficiency of Smad3 confers structural and functional protection against acute ischemic injury to the kidney. We speculate that these effects may be mediated through suppression of IL-6 production. Finally, we suggest that upregulation of Smad3 after an ischemic insult may contribute to the increased risk for chronic kidney disease that occurs after acute renal ischemia.

Original languageEnglish (US)
Pages (from-to)F436-F442
JournalAmerican Journal of Physiology - Renal Physiology
Volume301
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • Chronic kidney disease
  • Heme oxygenase-1
  • IL-6
  • TGF-β1

ASJC Scopus subject areas

  • Physiology
  • Urology

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