Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride.

Cheng HF, Wang JL, Zhang MZ, McKanna JA, Harris RC
J Clin Invest. 2000 106 (5): 681-8

PMID: 10974021 · PMCID: PMC381289 · DOI:10.1172/JCI10318

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.

MeSH Terms (22)

Animals Bumetanide Carrier Proteins Chlorides Cyclooxygenase 2 Gene Expression Regulation, Enzymologic Imidazoles Isoenzymes Kidney Cortex Kidney Glomerulus Kidney Tubules, Distal Loop of Henle Male Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Prostaglandin-Endoperoxide Synthases Rabbits Rats Rats, Sprague-Dawley Renin Sodium-Potassium-Chloride Symporters Sodium Chloride, Dietary

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