期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 48, 页码 37922-37929出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M006218200
关键词
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资金
- NIDDK NIH HHS [DK40042, DK39255, DK37448] Funding Source: Medline
Reducing luminal NaCl concentration in the macula densa region of the nephron stimulates renin secretion, and this response is blocked by a specific inhibitor of cyclooxygenase-2 (COX-2) (Traynor, T. R., Smart, A., Briggs, J. P., and Schnermann, J. (1999) Am. J. Physiol. Renal Physiol, 277, F706-710), To study whether low NaCl activates COX-2 activity or expression we clonally derived a macula densa cell line (MMDD1 cells) from SV-40 transgenic mice using fluorescence-activated cell sorting of renal tubular cells labeled with segment-specific fluorescent lectins, MMDD1 cells express COX-2, bNOS, NKCC2, and ROMK, but not Tamm-Horsfall protein, and showed rapid Rb-86(+) uptake that was inhibited by a reduction in NaCl concentration and by bumetanide or furosemide. Isosmotic exposure of MMDD1 cells to low NaCl (60 mM) caused a prompt and time-dependent stimulation of prostaglandin E-2 (PGE(2)) release that was prevented by the COX-2 specific inhibitor NS-398 (10 muM). Reducing NaCl to 60 and 6 mM for 16 h increased COX-2 expression in a chloride-dependent fashion. Low NaCl phosphorylated p38 kinase within 30 min and ERK1/2 kinases within 15 min without changing total MAP kinase levels. Low NaCl-stimulated PGE(2) release and COX-2 expression was inhibited by SE 203580 and PD 98059 (10 muM), inhibitors of p38 and ERK kinase pathways. We conclude that low chloride stimulates PGE(2) release and COX-2 expression in MMDD1 cells through activation of MAP kinases.
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