Effects of kynurenine metabolites on mesangial cell proliferation and gene expression.
In the present study, we examined the effects of kynurenine metabolites on cultured mesangial cells (MCs) and demonstrated for the first time that they affect MC proliferation and gene expression. Anthranilic acid and 3-hydroxy-DL-kynurenine suppressed MC proliferation by 32% and 43%, respectively at 10(-6) M compared to the control. In contrast, quinolinic acid and l-kynurenine promoted MC proliferation by 49% and 35% at 10(-8) M respectively, although promoting activities declined at higher concentrations. In addition, quinolinic acid upregulated the gene expression of platelet-derived growth factor-B, collagen type-Ialpha1, and collagen type-IValpha1. However, the gene expression of hepatocyte growth factor (HGF) was downregulated. We further examined the gene expressions in the glomeruli of high serum IgA (HIGA) mice with IgA nephropathy using microarray technology and found that the gene expression of insulin-like growth factor-1 was higher, but that of HGF was lower at 40 weeks of age compared to 8 weeks of age. In Balb/c mice, the gene expression of three kynurenine pathway enzymes (kynurenine aminotransferase I, kynurenine aminotransferase II, and quinolinate phospho-ribosyltransferase) increased 2- to 3.5-fold, whereas those in HIGA mice did not change significantly. These results suggest that abnormalities in the kynurenine pathway are associated with the dysfunction of MCs and progression of chronic kidney diseases.
Yoshimura
Hiromitsu
H
Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama-shi, Saitama, Japan. hi.yoshimura@po.rd.taisho.co.jp
Sakai
Takayuki
T
Kuwahara
Yusuke
Y
Ito
Masayoshi
M
Tsuritani
Katsuki
K
Hirasawa
Yasushi
Y
Nagamatsu
Tadashi
T
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007737:Kynurenine / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis
D007737:Kynurenine; D017228:Hepatocyte Growth Factor