Kidney-specific genetic deletion of both AMPK α-subunits causes salt and water wasting.
AMP-activated kinase (AMPK) controls cell energy homeostasis by modulating ATP synthesis and expenditure. In vitro studies have suggested AMPK may also control key elements of renal epithelial electrolyte transport but in vivo physiological confirmation is still insufficient. We studied sodium renal handling and extracellular volume regulation in mice with genetic deletion of AMPK catalytic subunits. AMPKα1 knockout (KO) mice exhibit normal renal sodium handling and a moderate antidiuretic state. This is accompanied by higher urinary aldosterone excretion rates and reduced blood pressure. Plasma volume, however, was found to be increased compared with wild-type mice. Thus blood volume is preserved despite a significantly lower hematocrit. The lack of a defect in renal function in AMPKα1 KO mice could be explained by a compensatory upregulation in AMPK α2-subunit. Therefore, we used the Cre-loxP system to knock down AMPKα2 expression in renal epithelial cells. Combining this approach with the systemic deletion of AMPKα1 we achieved reduced renal AMPK activity, accompanied by a shift to a moderate water- and salt-wasting phenotype. Thus we confirm the physiologically relevant role of AMPK in the kidney. Furthermore, our results indicate that in vivo AMPK activity stimulates renal sodium and water reabsorption.
Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain.
Yoskaly
Y
Lazo-Fernández
Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain.
Goretti
G
Baile
Department of Cellular Biology and Biochemistry University of Zaragoza, Zaragoza, Spain.|IIS Aragón. Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
Patricia
P
Meade
IIS Aragón. Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
Pilar
P
Torcal
IIS Aragón. Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
Laura
L
Martínez
Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain.
Carmen
C
Ibañez
Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain.
Maria Luisa
ML
Bernal
INSERM, U1016, Institut Cochin, Paris, France.|CNRS (UMR 8104), Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Benoit
B
Viollet
Department of Pharmacology and Physiology, University of Zaragoza, Zaragoza, Spain; igimenez@unizar.es.|IIS Aragón. Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
Ignacio
I
Giménez
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D001810:Blood Volume / Q000235:genetics; D004326:Drinking / Q000235:genetics*; D004435:Eating / Q000235:genetics; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D014882:Water-Electrolyte Balance / Q000235:genetics*
C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases
AMP-activated kinase; Cre-lox; blood pressure; extracellular volume regulation; renal function