title: Genetic deficiency of Smad3 protects against murine ischemic acute kidney injury.
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-α, 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.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: Gina M
authors.initials: GM
authors.lastname: Warner
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005260:Female; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse