Fatty acid dependent regulation of renin transcription by nuclear hormone receptor HNF‐4

Abstract

Production and release of renin are pivotal in controlling the Renin‐angiotensin‐system (RAAS), a main long‐term regulator of blood pressure and electrolyte homeostasis. In this context, the regulation of renin transcription by hormonal and nutritional agents is of fundamental interest.Fatty acid dependent transcription factors LXRalpha and PPARgamma have already been shown to affect renin gene transcription. We focussed our attention on another member of the nuclear hormone receptor family, HNF‐4, which is bound by fatty acyl CoA modulating its transcriptional activity. In co‐transfection experiments, HNF‐4 activated a luciferase reporter construct containing 5797bp upstream the transcriptional start site of the renin gene more than five‐fold. This effect could be completely abolished by the addition of omega3 fatty acids at a concentration of 500μM. Using computational methods, we identified five potential binding sites for HNF‐4 in this sequence. There is first evidence that HNF‐4 binds to these sites depending on the presence of fatty acyl CoAs.As HNF‐4 is expressed abundantly in proximal tubular cells our results could shed light on the regulation of local proximal tubular RAAS by fatty acids, indicating a new potential role of HNF‐4 in the kidney. Down‐regulation of renin gene expression may contribute to the antihypertensive effect of fish oil omega3 fatty acids.