Tumor necrosis factor-alpha inhibits renin gene expression.
Renin, produced in renal juxtaglomerular (JG) cells, is a fundamental regulator of blood pressure. Accumulating evidence suggests that cytokines may directly influence renin production in the JG cells. TNF-alpha, which is one of the key mediators in immunity and inflammation, is known to participate in the control of vascular proliferation and contraction and hence in the pathogenesis of cardiovascular diseases. Thus TNF-alpha may exert its effects on the cardiovascular system through modulation of renal renin synthesis. Therefore we have tested the effect of TNF-alpha on renin transcription in As4.1 cells, which represent transformed mouse JG cells, and in native mouse JG cells in culture. Renin gene expression was also determined in mice lacking the gene for TNF-alpha (TNF-alpha knockout mice). TNF-alpha inhibited renin gene expression via an inhibition of the transcriptional activity, targeting the proximal 4.1 kb of the renin promoter in As4.1 cells. TNF-alpha also attenuated forskolin-stimulated renin gene expression in primary cultures of mouse JG cells. Mice lacking the TNF-alpha gene had almost threefold higher basal renal renin mRNA abundance relative to the control strain. The general physiological regulation of renin expression by salt was not disturbed in TNF-alpha knockout mice. Our data suggest that TNF-alpha inhibits renin gene transcription at the cellular level and thus may act as a modulator of renin synthesis in (physio)pathological situations.
Todorov
Vladimir
V
Institut für Physiologie I, Universität Regensburg, D-93040 Regensburg, Germany. vladimir.todorov@vkl.uni-regensburg.de
Müller
Markus
M
Schweda
Frank
F
Kurtz
Armin
A
D000818:Animals; D002460:Cell Line; D003864:Depression, Chemical; D005786:Gene Expression Regulation / Q000187:drug effects*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023282:Nuclease Protection Assays; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011863:Radioimmunoassay; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D012083:Renin