ERRgamma regulates cardiac, gastric, and renal potassium homeostasis.
Energy production by oxidative metabolism in kidney, stomach, and heart, is primarily expended in establishing ion gradients to drive renal electrolyte homeostasis, gastric acid secretion, and cardiac muscle contraction, respectively. In addition to orchestrating transcriptional control of oxidative metabolism, the orphan nuclear receptor, estrogen-related receptor gamma (ERRgamma), coordinates expression of genes central to ion homeostasis in oxidative tissues. Renal, gastric, and cardiac tissues subjected to genomic analysis of expression in perinatal ERRgamma null mice revealed a characteristic dysregulation of genes involved in transport processes, exemplified by the voltage-gated potassium channel, Kcne2. Consistently, ERRgamma null animals die during the first 72 h of life with elevated serum potassium, reductions in key gastric acid production markers, and cardiac arrhythmia with prolonged QT intervals. In addition, we find altered expression of several genes associated with hypertension in ERRgamma null mice. These findings suggest a potential role for genetic polymorphisms at the ERRgamma locus and ERRgamma modulators in the etiology and treatment of renal, gastric, and cardiac dysfunction.
Alaynick
William A
WA
Gene Expression Laboratory and the Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. alaynick@salk.edu
Way
James M
JM
Wilson
Stephanie A
SA
Benson
William G
WG
Pei
Liming
L
Downes
Michael
M
Yu
Ruth
R
Jonker
Johan W
JW
Holt
Jason A
JA
Rajpal
Deepak K
DK
Li
Hao
H
Stuart
Joan
J
McPherson
Ruth
R
Remlinger
Katja S
KS
Chang
Ching-Yi
CY
McDonnell
Donald P
DP
Evans
Ronald M
RM
Billin
Andrew N
AN
D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D015992:Body Mass Index; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006321:Heart / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013270:Stomach / Q000473:pathology
C490917:ESRRG protein, human; C490916:Esrrg protein, mouse; C489620:Kcne2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D011960:Receptors, Estrogen; D011188:Potassium