Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury

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

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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)
JournalAmerican Journal of Physiology - Renal Physiology
Volume301
Issue number2
DOIs
StatePublished - Aug 2011

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Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Urology

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