DOWN-REGULATION OF RENIN GENE-EXPRESSION BY INTERLEUKIN-1

The As4.1 cell Line was established from a mouse kidney tumor by trans gene-targeted tumorogenesis. These cells express high levels of renin mRNA from their endogenous renin gene and release approximately eightf old-more prorenin than active renin in culture. Levels of renin mRNA i n As4.1 cells are decreased in a dose-dependent manner by the addition of physiological concentrations of cytokine interleukin-1 to the medi a. Stability of renin mRNA and initial rates of release of active reni n and prorenin were not significantly altered by interleukin-l. In con trast, transcription initiated from a construct that consisted of 4.1 kilobases of renin 5' flanking sequence fused to a reporter gene (chlo ramphenicol acetyltransferase) was markedly inhibited by interleukin-1 . On the basis of our findings, we conclude that downregulation of ren in 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 p hysiological relevance of this regulation is related to the events tha t occur during septic shock, characterized by hypotension, cardiovascu lar 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 bel ieved to be mediated by the combined action of many modulators includi ng cytokines, and data presented here suggest direct involvement of in terleukin-1 in this process.