Physiological Genomics Identifies Estrogen-Related Receptor alpha as a Regulator of Renal Sodium and Potassium Homeostasis and the Renin-Angiotensin Pathway

Estrogen-related receptor alpha (ERR alpha) is an orphan nuclear receptor highly expressed in the kidney, an organ playing a central role in blood pressure regulation through electrolyte homeostasis and the renin-angiotensin system. Physiological analysis revealed that, relative to wild-type mice, ERR alpha null mice are hypotensive despite significant hypernatremia, hypokalemia, and slight hyperreninemia. Using a combination of genome-wide location analysis and expression profiling, we demonstrate that ERR alpha regulates the expression of channels involved in renal Na+ and K+ handling (Scnn1a, Atp1a1, Atp1b1) and altered in Bartter syndrome (Bsnd, Kcnq1). In addition, ERR alpha regulates the expression of receptors implicated in the systemic regulation of blood pressure (Ghr, Gcgr, Lepr, Npy1r) and of genes within the renin-angiotensin pathway (Ren1, Agt, Ace2). Our study thus identifies ERR alpha as a pleiotropic regulator of renal control of blood pressure, renal Na+/K+ homeostasis, and renin-angiotensin pathway and suggests that modulation of ERR alpha activity could represent a potential avenue for the management of hypertension. (Molecular Endocrinology 24: 22-32, 2010)