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 (ERRalpha) 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, ERRalpha 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 ERRalpha regulates the expression of channels involved in renal Na(+) and K(+) handling (Scnn1a, Atp1a1, Atp1b1) and altered in Bartter syndrome (Bsnd, Kcnq1). In addition, ERRalpha 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 ERRalpha as a pleiotropic regulator of renal control of blood pressure, renal Na(+)/K(+) homeostasis, and renin-angiotensin pathway and suggests that modulation of ERRalpha activity could represent a potential avenue for the management of hypertension.
Tremblay
Annie M
AM
Rosalind and Goodman Cancer Centre, McGill University, Montréal, Québec, Canada.
Dufour
Catherine R
CR
Ghahremani
Majid
M
Reudelhuber
Timothy L
TL
Giguère
Vincent
V
D000818:Animals; D001477:Bartter Syndrome / Q000503:physiopathology; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023281:Genomics / Q000379:methods; D007022:Hypotension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016623:Ion Pumps / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000235:genetics*; D012982:Sodium, Dietary / Q000009:adverse effects; D014882:Water-Electrolyte Balance; D000097983:ERRalpha Estrogen-Related Receptor
D016623:Ion Pumps; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D012982:Sodium, Dietary; D000097983:ERRalpha Estrogen-Related Receptor