Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

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 Krüppel-like factor 4 (Klf4) regulates vascular cell adhesion molecule 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-Cre mice 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.

Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

“…Similarly, palmitic acid (PA) obviously decreased the levels of KLF4 gene (Figure 2A) and protein (Figure 2B-2C) in mouse renal endothelial cells. Furthermore, consistent with a previous finding in the mouse model with acute kidney injury,18 overexpression of Klf4 also inhibited adhesion cytokines, including VCAM-1 and ICAM-1 (Figure 2H, P < .05). Figure S1 showed that adeno-associated virus (AAV) encoding Klf4 successfully overexpressed KLF4 mRNA (Figure S1A) and protein levels (Figure S1B-1C) in endothelial F I G U R E 1 Renal KLF4 level is closely associated with renal dysfunction in obese mice.…”

“…13 More importantly, studies also found KLF4 functioned as a suppressor of renal fibrogenesis. 18 Interestingly, current study also found the crucial role of KLF4 in obesity-related renal injuries. 18 Interestingly, current study also found the crucial role of KLF4 in obesity-related renal injuries.…”

“…[12][13][14] Xiao et al and Chen et al found KLF4 functioned as a suppressor of renal fibrogenesis. 18 However, the role and molecular regulating signalling of KLF4 in obesity-related nephropathy are unknown. 17 Besides, endothelial KLF4 improved renal function and determined the benefits of statin in ischaemic acute kidney injury by decreasing inflammatory response.…”

Krüppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility

“…For in vivo validation of flow-induced Ch25h, we isolated intima, which contains the endothelium 30, 31 , from the aortic arch (AA) and thoracic aorta (TA) of C57BL/6 mice. The flow pattern in AA and TA are atheroprone and atheroprotective, respectively 32 .…”

“…In parallel to atheroprotective flow, vasoprotective drugs (e.g., statins) also induce KLF4 31, 33 . Thus, we postulated that statins may also achieve its pleotropic effects in ECs in part through the increase of Ch25h.…”