Angiotensin II induces tumor necrosis factor-α expression and release from cultured human podocytes

High levels of both angiotensin (Ang) II and tumor necrosis factor (TNF)-alpha have been implicated in the pathogenesis of glomerular injury by affecting podocytes. The aim of this study was to investigate the Ang II-TNF-alpha relationship in human podocytes. Immortalized podocytes were exposed to Ang II for 6 days in the absence or presence of either losartan or PD123,319 (both at 100 nM), AT(1) and AT(2) receptor antagonists, respectively. Ang II, after at least 72 h of repeated treatment, increased basal TNFA gene expression and cytokine release with a biphasic pattern and maximum response at 10 nM. Losartan dampened the effects of Ang II on TNF-alpha production throughout the experimental period, demonstrating an AT(1) receptor contribution. PD123,319 affected the second TNF-alpha production peak, showing also an AT(2) receptor contribution. Moreover, Ang II causes tumor necrosis factor receptor (TNFR) 1 and TNFR2 over-expression in a time-dependent manner. The functional interaction between Ang II and TNF-alpha was demonstrated when the pro-proliferative effect of Ang II was antagonized by a neutralizing TNF-alpha antibody. Our results show a functional interaction between Ang II and TNF-alpha and implicate this cytokine as a mediator in Ang II long-term pathoadaptive podocytes changes.