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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/F1556    most recent 00010.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ma, F. Y. Articles by Nikolic-Paterson, D. J. Search for Related Content PubMed PubMed Citation Articles by Ma, F. Y. Articles by Nikolic-Paterson, D. J.

MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

¹Department of Nephrology and ²Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia; ³Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut; and ⁴Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 5 January 2007 ; accepted in final form 3 August 2007

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3–/– mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3–/– kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3–/– kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3–/– UUO mice. Furthermore, cultured Mkk3–/– tubular epithelial cells showed resistance to H₂O₂-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3–/– mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3–/– UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

MKK6; macrophage; MCP-1; fibrosis

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