Endothelial krüppel-like factor 4 mediates the protective effect of statins against ischemic AKI

Tadashi Yoshida, Maho Yamashita, Mieko Iwai, Matsuhiko Hayashi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Endothelial cells participate in the pathophysiology of ischemic AKI by increasing the expression of cell adhesion molecules and by recruiting inflammatory cells.We previously showed that endothelial Krüppellike factor 4 (Klf4) regulates vascular cell adhesionmolecule 1 (Vcam1) expression and neointimal formation after carotid injury. In this study, we determined whether endothelial Klf4 is involved in ischemic AKI using endothelial Klf4 conditional knockout (Klf4 cKO) mice generated by breeding Tek-Cremice and Klf4 floxed mice. Klf4 cKO mice were phenotypically normal before surgery. However, after renal ischemia-reperfusion injury, Klf4 cKO mice exhibited elevated serum levels of urea nitrogen and creatinine and aggravated renal histology compared with those of Klf4 floxed controls. Moreover, Klf4 cKO mice exhibited enhanced accumulation of neutrophils and lymphocytes and elevated expression of cell adhesion molecules, including Vcam1 and Icam1, in injured kidneys. Notably, statins ameliorated renal ischemia-reperfusion injury in control mice but not in Klf4 cKO mice. Mechanistic analyses in cultured endothelial cells revealed that statins increased KLF4 expression and that KLF4 mediated the suppressive effect of statins on TNFa- induced VCAM1 expression by reducing NF-kB binding to the VCAM1 promoter. These results provide evidence that endothelial Klf4 is renoprotective and mediates statin-induced protection against ischemic AKI by regulating the expression of cell adhesion molecules and concomitant recruitment of inflammatory cells.

Original languageEnglish
Pages (from-to)1379-1388
Number of pages10
JournalJournal of the American Society of Nephrology
Volume27
Issue number5
DOIs
Publication statusPublished - 2016 May

ASJC Scopus subject areas

  • Nephrology

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