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

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Abstract
The effects of angiotensin II (ANG II) on tumor necrosis factor-α (TNF) production were determined in freshly isolated tubules from the medullary thick ascending limb (MTAL). ANG II (10−9M) 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 on86Rb uptake, depending on the exposure time of the tubules to the peptide and the doses used. Low-dose ANG II (10−11M) increased86Rb 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 (10−6M) inhibited MTAL86Rb uptake, irrespective of incubation time. Uptake of86Rb was inhibited by ∼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 PGE2by inhibition of cyclooxygenase with indomethacin. We conclude that ANG II regulates TNF production in the MTAL, an interaction that affects86Rb uptake via an eicosanoid-dependent mechanism in this nephron segment.