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 five- to sixfold. ANG II also increased prostaglandin E2 (PGE2) production by the MTAL in a dose-dependent manner and exerted biphasic differential effects on 86Rb uptake, depending on the exposure time of the tubules to the peptide and the doses used. Low-dose ANG II (10(-11) M) increased 86Rb 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 86Rb uptake, irrespective of incubation time. Uptake of 86Rb was inhibited by approximately 60% in MTAL tubules that were challenged for 3 h with ANG II. The inhibitory action of ANG II was prevented by eliminating the participation of either TNF with antisera to the cytokine or PGE2 by inhibition of cyclooxygenase with indomethacin. We conclude that ANG II regulates TNF production in the MTAL, an interaction that affects 86Rb uptake via an eicosanoid-dependent mechanism in this nephron segment.