The eicosanoid factor: a determinant of individuality of nephron segments

Nephron function is segmented, each segment has characteristic transport mechanisms and individual eicosanoid profiles. The transport function of the medullary thick ascending limb of Henle's loop (mTAL) establishes the osmolar gradient upon which extra cellular fluid volume (ECFV) conservation depends. The overriding importance of the mTAL to regulation of ECFV is evident in the diuretic-natriuretic potency of furosemide-like agents which target the mTAL.

The mTAL has been shown to be heavily invested with cytochrome P450 monooxygenases (CYP), chiefly omega/omega-1 hydroxylase activity, that generate 19- and 20-hydroxyeicosatetraenoic acid (HETEs). However, displacement of omega hydroxylase by an inducible cyclooxygenase mechanism (COX-2) can be effected by several interventions: long-term infusion of angiotensin II (ANG II), adrenalectomy and elevated extracellular Ca2+ concentrations. This switching mechanism (CYP > COX-2) has been shown to be dependent on activation of tumor necrosis factor alpha (TNFalpha) by ANG II. It represents a long-term adaptive mechanism of the mTAL with production of PGE2 whereas in the short-term, ANG 11 increases 20-HETE synthesis by the mTAL. The effect of Ca2+ on mTAL eicosanoid-related mechanisms provides an explanation for the natriuretic response to hypercalcemia and diminished ability to concentrate urine.

The expression of COX-2 in the TAL has been linked to activation of the renin-angiotensin system, glucocorticoid deficiency and hypercalcemia, all of which operate through a mechanism in which production of TNFalpha by the TAL is pivotal.