TNFα regulates renal COX-2 in the rat thick ascending limb (TAL)

We have examined cyclooxygenase (COX)-2-dependent mechanisms in preglomerular microvessels and the thick ascending limb (TAL). These renal structures are linchpins in the regulation of the renal circulation and extracellular fluid volume. Cytochrome P450 monooxygenases are the principal oxygenases in the TAL segment; however, COX-2 can be expressed in the TAL, as when challenged by angiotensin II. Glucocorticoids also affect the expression and activity of oxygenases in the TAL. Before adrenalectomy, <2% TAL cells expressed COX-2; after, >30% of TAL cells expressed COX-2. Recruitment of COX-2 is initiated in the renal cortex and proceeds to the medulla associated with: (1) COX-2 mRNA accumulation; (2) increased COX-2 expression; and (3) a two-fold increase in PGE₂ production by cortical microsomes. These changes were nullified by dexamethasone. COX-2 mRNA, protein expression and PGE₂ synthesis in the TAL are also increased in response to increased extracellular Ca²⁺. The Ca²⁺ sensing receptor is G-protein coupled and responds to changes in extracellular Ca²⁺ concentration by increasing protein kinase C activity to produce expression of COX-2. Thus, multiple signaling pathways contribute to COX-2 expression in TAL cells.