The inflammation-lipocalin 2 axis may contribute to the development of chronic kidney disease.
BACKGROUND
Chronic kidney disease (CKD) is an important risk factor for coronary heart disease, and previous studies indicated the involvement of low-grade inflammation in the pathogenesis of CKD.


METHODS
The study was designed to (i) identify and confirm genes and their products upregulated in mesangial cells cocultured with endotoxin-stimulated macrophages and (ii) determine the clinical relevance of genes and proteins upregulated in mesangial cells under inflammatory conditions by an epidemiological approach.


RESULTS
DNA microarray analysis revealed upregulated expression of many genes and their products including several cytokines and chemokines, as well as the inflammatory marker, lipocalin 2 gene. The gene expression and protein upregulation of lipocalin 2 were synergistically affected by endotoxin and tumor necrosis factor (TNF)-α stimulation. In human studies, lipocalin 2 level was significantly associated with creatinine (r = 0.419, P < 0.001) and negatively associated with eGFR (r = -0.365, P < 0.001). Multiple logistic regression analysis revealed a significant association between lipocalin 2 and soluble tumor necrosis factor receptor 2 (sTNF-R2), eGFR and uric acid in general subjects attending regular annual medical check-up (n = 420). When subjects with diabetes were excluded from the analysis, lipocalin 2 remained associated with sTNF-R2, eGFR and uric acid.


CONCLUSIONS
Since an activated TNF system, as demonstrated by elevated sTNF-R2, and elevated uric acid were recently implicated in an elevated CKD risk, we conclude that inflammation could play an important role in the pathogenesis of CKD, and that lipocalin 2 is a potential universal marker for impaired kidney function. Furthermore, the results obtained by the current microarray analysis could improve the understanding of gene profiles associated with the pathophysiology of CKD under inflammatory conditions.
Department of Dental Science for Health Promotion, Hiroshima University Institute for Biomedical and Health Sciences, Hiroshima, Japan.
Atsushi
A
Hashikata
Akiko
A
Yamashita
Shigeki
S
Suzuki
Shintaro
S
Nagayasu
Takanori
T
Shinjo
Ataru
A
Taniguchi
Mitsuo
M
Fukushima
Yoshikatsu
Y
Nakai
Kazuko
K
Nin
Naoya
N
Watanabe
Tomoichiro
T
Asano
Yoshimitsu
Y
Abiko
Akifumi
A
Kushiyama
Shoichiro
S
Nagasaka
Fusanori
F
Nishimura
D000209:Acute-Phase Proteins / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D059467:Transcriptome
D000209:Acute-Phase Proteins; D015415:Biomarkers; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; D003404:Creatinine
CKD; inflammation; lipocalin 2; macrophages; mesangial cells