Angiotensin II induces TNF production by the thick ascending limb: functional implications

The effects of angiotensin II (ANG II) on tumor necrosis factor-alpha (TNF) production were determined in freshly isolated tubules from the medullary thick ascending Limb (MTAL). ANG II (10(-9) M) increased the accumulation of TNF mRNA associated with enhanced production of TNF by approximately vs-to sixfold. ANG II also increased prostaglandin E(2) (PGE(2)) production by the MTAL in a dose-dependent manner and exerted biphasic differential effects on (86)Rb uptake, depending on the exposure time of the tubules to the peptide and the doses used. Low-dose ANG II (10(-11) M) increased (86)Rb uptake by MTAL tubules after a "short-term" (15 min) challenge, whereas uptake was inhibited after a "long-term" (3 h) incubation period. High-dose ANG II (10(-6) M) inhibited MTAL (86)Rb uptake, irrespective of incubation time. Uptake of (86)Rb was inhibited by similar to 60% in MTAL tubules that were challenged for 3 h with ANG II. The inhibitory ad-ion of ANG II was prevented by eliminating the participation of either TNF with antisera to the cytokine or PGE(2) by inhibition of cyclooxygenase with indomethacin. We conclude that ANC; II regulates TNF production in the MTAL, an interaction that affects (86)Rb uptake via an eicosanoid-dependent mechanism in this nephron segment.