Angiotensin II induces tumor necrosis factor-α expression and release from cultured human podocytes.
OBJECTIVE
High levels of both angiotensin (Ang) II and tumor necrosis factor (TNF)-α have been implicated in the pathogenesis of glomerular injury by affecting podocytes. The aim of this study was to investigate the Ang II-TNF-α relationship in human podocytes.


METHODS
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.


RESULTS
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-α production throughout the experimental period, demonstrating an AT(1) receptor contribution. PD123,319 affected the second TNF-α 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-α was demonstrated when the pro-proliferative effect of Ang II was antagonized by a neutralizing TNF-α antibody.


CONCLUSIONS
Our results show a functional interaction between Ang II and TNF-α and implicate this cytokine as a mediator in Ang II long-term pathoadaptive podocytes changes.
Dipartimento di Scienza e Tecnologia del Farmaco, University of Turin, Corso Raffaello 33, 10125 Turin, Italy. ariannacarolina.rosa@unito.it
Arianna Carolina
AC
Rosa
Lorenza
L
Rattazzi
Gianluca
G
Miglio
Massimo
M
Collino
Roberto
R
Fantozzi
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan