Downregulation of renin gene expression by interleukin-1

The As4.1 cell Line was established from a mouse kidney tumor by transgene-targeted tumorogenesis. These cells express high levels of renin mRNA from their endogenous renin gene and release approximately eightfold-more prorenin than active renin in culture. Levels of renin mRNA in As4.1 cells are decreased in a dose-dependent manner by the addition of physiological concentrations of cytokine interleukin-1 to the media. Stability of renin mRNA and initial rates of release of active renin and prorenin were not significantly altered by interleukin-l. In contrast, transcription initiated from a construct that consisted of 4.1 kilobases of renin 5' flanking sequence fused to a reporter gene (chloramphenicol acetyltransferase) was markedly inhibited by interleukin-1. On the basis of our findings, we conclude that downregulation of renin synthesis caused by interleukin-l occurs primarily at the level of transcription and that DNA sequence or sequences mediating that effect are positioned within 4.1 kilobases upstream of the renin gene. The physiological relevance of this regulation is related to the events that occur during septic shock, characterized by hypotension, cardiovascular collapse, multiple organ failure, and high mortality. Unexpectedly, hypotension associated with septic shock does not lead to activation of the renin-angiotensin system. The hypotension in septicemia is believed to be mediated by the combined action of many modulators including cytokines, and data presented here suggest direct involvement of interleukin-1 in this process.