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

• Published in: The Journal of clinical investigation 2000-09, Vol.106 (5), p.681-688
• Main Authors: Cheng, H F, Wang, J L, Zhang, M Z, McKanna, J A, Harris, R C
• Format: Article
• Language: English
• Subjects: Animals; Bumetanide - pharmacology; Carrier Proteins - antagonists & inhibitors; Chlorides - metabolism; Cyclooxygenase 2; Gene Expression Regulation, Enzymologic; Imidazoles - pharmacology; Isoenzymes - biosynthesis; Kidney Cortex - enzymology; Kidney Glomerulus - enzymology; Kidney Tubules, Distal - enzymology; Loop of Henle; Male; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases - biosynthesis; Rabbits; Rats; Rats, Sprague-Dawley; Renin - biosynthesis; Sodium Chloride, Dietary - pharmacology; Sodium-Potassium-Chloride Symporters
• ISSN: 0021-9738
• 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.