Klf10 deficiency in mice exacerbates pulmonary inflammation by increasing expression of the proinflammatory molecule NPRA.
KLF10 is a transforming growth factor (TGF)-β/Smad downstream regulated gene. KLF10 binds to the promoter of target genes and mimics the effects of TGF-β as a transcriptional factor. In our laboratory, we noted that Klf10 deficiency in mice is associated with significant inflammation of the lungs. However, the precise mechanism of this association remains unknown. We previously identified NPRA as a target gene potentially regulated by KLF10 through direct binding; NPRA knockout have known that prevented lung inflammation in a mouse model of allergic asthma. Here, we further explored the regulatory association between KLF10 and NPRA on the basis of the aforementioned findings. Our results demonstrated that KLF10 acts as a transcriptional repressor of NPRA and that KLF10 binding reduces NPRA expression in vitro. Compared with wild-type mice, Klf10-deficient mice were more sensitive to lipopolysaccharide or ovalbumin challenge and showed more severe inflammatory histological changes in the lungs. Moreover, Klf10-deficient mice showed pulmonary neutrophil accumulation. These findings collectively reveal the precise site where KLF10 signaling affects pulmonary inflammation by attenuating NPRA expression. They also verify the importance of KLF10 and atrial natriuretic peptide/NPRA in exerting influences on chronic pulmonary disease pathogenesis.
Department of Pediatrics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine,Taipei Medical University, Taiwan.
Liang-Ti
LT
Huang
Laboratory Animal Center, Taipei Medical University, Taipei, Taiwan.
Hsuen-Wen
HW
Chang
PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan.
Min-Ju
MJ
Wu
PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan.
Yong-Tzuo
YT
Lai
Laboratory Animal Center, Taipei Medical University, Taipei, Taiwan.
Wen-Chi
WC
Wu
PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Taiwan.
Winston C Y
WCY
Yu
PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan. Electronic address: vinhschang@tmu.edu.tw.
Vincent H S
VHS
Chang
D000818:Animals; D002199:Capillary Permeability; D051765:Early Growth Response Transcription Factors / Q000172:deficiency*; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology; D011014:Pneumonia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
D051765:Early Growth Response Transcription Factors; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A
Atrial natriuretic peptide; Inflammation; Krüppel-like factor 10; Natriuretic peptide receptor A; Pulmonary disease