Abstract 3477: Liver X Receptor-Alpha is a Regulator of the Renal and Cardiac Renin-Angiotensin System
It was previously shown that Liver X receptor(LXR)-α is a cAMP responsive regulator of renin transcription. Although LXR-α was shown to induce renin transcription in vitro, we showed that in vivo, the synthetic LXR agonist T0901317 (T09) blunts renin transcription and transcription of other RAS components. To study these effects in more detail, we used LXR-α deficient mice (KO mice) to study ISO-induced RAS activation. KO mice and their wildtype (WT) littermates were treated with isoproterenol (ISO) (to activate the RAS), T09 or both ISO+T09 for 7 days (n=8). Heart and kidneys were assayed with quantitative RT-PCR and with western blot for expression of various elements of the RAS (renin, ACE, and AT1R). Binding of LXR-α to a specific element in the renin promoter (CNRE) was determined by EMSA. Low dose ISO treatment, not associated with an increase in blood pressure or heart rate, caused an increase in renal renin mRNA (0.64±0.16 vs 3.48±1.13, p<0.01) and renin protein (0.24±0.10 vs 2.75±1.01, p<0.05) in WT mice. The ISO-induced increase of renin mRNA/protein was abolished by co-treatment with T09 (mRNA: 0.34±0.17, protein: 1.16±0.47). In LXR-α KO mice, ISO caused no significant increase in renal renin mRNA (0.66±0.13 vs 1.90±1.14) or protein (1.51±0.55 vs 0.74±0.04). Treatment with both ISO and T09 decreased renal ACE mRNA (0.59±0.49 vs 2.84±1.12, p< 0.05) and ACE protein (1.21±0.32 vs 2.51±0.77, p< 0.05) in WT mice compared to ISO-treated mice, but no effect was found in KO mice (mRNA: 3.00±0.70 vs 1.65±0.60, protein: 2.18±0.69 vs 1.46±0.25). ACE mRNA expression was also reduced in hearts of WT mice treated with ISO and T09 compared with WT mice on ISO alone (p<0.05). Again, this effect was not found in KO mice. EMSA showed that the ISO-induced binding of LXR-α to the CNRE is weakened in mice co-treated with T09. In KO mice, no increase in LXR-α-CNRE binding of was found after ISO treatment. LXR activation by T09 blunts ISO induced activation of the entire RAS cascade, both in the kidney and the heart. This effect was not found in KO mice, suggesting that this is a LXR-α-specific effect. These findings suggest that LXR-α plays an eminent role in RAS activation, and therapies aimed to stimulate LXR may modulate the RAS.