Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride.
We have previously shown that in renal cortex, COX-2 expression is localized to macula densa and surrounding cortical thick ascending limb of Henle (cTALH). Dietary salt restriction increases local expression of COX-2, which mediates renin production and secretion. Given that decreased luminal chloride [Cl(-)] at the level of the macula densa increases renin production and secretion, we investigated the role of extracellular ion concentration on COX-2 expression. Quiescent rabbit cTALH cells were incubated in a physiological salt solution containing high or low levels of NaCl. Immunoreactive COX-2 expression increased significantly in the low NaCl solution. COX-2 expression also increased after administration of the Na(+)/K(+)/2Cl(-) cotransport inhibitor, bumetanide. Selective substitution of chloride led to increased COX-2 expression, whereas selective substitution of sodium had no effect. The p38 MAP kinase inhibitor PD169316 decreased low NaCl-induced COX-2 expression. Low-salt or low-chloride medium induced cultured cTALH to accumulate >/= 3-fold higher levels of pp38, the activated (phosphorylated) form of p38; low-salt medium also increased pJNK and pERK levels. Feeding rats a low-salt diet for 14 days induced a significant increase in renal cortical pp38 expression, predominantly in the macula densa and cTALH. These results suggest that reduced extracellular chloride leads to increased COX-2 expression, which may be mediated by activation of a p38-dependent signaling pathway.
Cheng
H F
HF
George M. O'Brien Kidney and Urologic Diseases Center and Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Wang
J L
JL
Zhang
M Z
MZ
McKanna
J A
JA
Harris
R C
RC
D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002712:Chlorides / Q000378:metabolism*; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D007672:Kidney Cortex / Q000201:enzymology*; D007678:Kidney Glomerulus / Q000201:enzymology; D007686:Kidney Tubules, Distal / Q000201:enzymology; D008138:Loop of Henle; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000096:biosynthesis; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D028021:Sodium-Potassium-Chloride Symporters; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D002712:Chlorides; D007093:Imidazoles; D007527:Isoenzymes; D017673:Sodium Chloride, Dietary; D028021:Sodium-Potassium-Chloride Symporters; D002034:Bumetanide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D012083:Renin; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole