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 b y approximately vs-to sixfold. ANG II also increased prostaglandin E-2 (PGE(2)) production by the MTAL in a dose-dependent manner and exerte d biphasic differential effects on Rb-86 uptake, depending on the expo sure time of the tubules to the peptide and the doses used. Low-dose A NG II (10(-11) M) increased Rb-86 uptake by MTAL tubules after a ''sho rt-term'' (15 min) challenge, whereas uptake was inhibited after a ''l ong-term'' (3 h) incubation period. High-dose ANG II (10(-6) M) inhibi ted MTAL Rb-86 uptake, irrespective of incubation time. Uptake of Rb-8 6 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 cyto kine or PGE(2) by inhibition of cyclooxygenase with indomethacin. We c onclude that ANC; II regulates TNF production in the MTAL, an interact ion that affects Rb-86 uptake via an eicosanoid-dependent mechanism in this nephron segment.