Dopamine and angiotensin type 2 receptors cooperatively inhibit sodium transport in human renal proximal tubule cells.
Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D(1)-like receptors (D(1)R/D(5)R) and the angiotensin type 2 receptor (AT(2)R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D(1)R/D(5)R stimulation increased plasma membrane AT(2)R 4-fold via a D(1)R-mediated, cAMP-coupled, and protein phosphatase 2A-dependent specific signaling pathway. D(1)R/D(5)R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal-regulated kinase, an effect that was partially reversed by an AT(2)R antagonist. Fenoldopam did not increase AT(2)R recruitment in renal proximal tubule cells with D(1)Rs uncoupled from adenylyl cyclase, suggesting a role of cAMP in mediating these events. D(1)Rs and AT(2)Rs heterodimerized and cooperatively increased cAMP and cGMP production, protein phosphatase 2A activation, sodium-potassium-ATPase internalization, and sodium transport inhibition. These studies shed new light on the regulation of renal sodium transport by the dopaminergic and angiotensin systems and potential new therapeutic targets for selectively treating hypertension.
University of Virginia, Charlottesville, VA 22908, USA. jjg5b@virginia.edu
John J
JJ
Gildea
Xiaoli
X
Wang
Neema
N
Shah
Hanh
H
Tran
Michael
M
Spinosa
Robert
R
Van Sciver
Midori
M
Sasaki
Junichi
J
Yatabe
Robert M
RM
Carey
Pedro A
PA
Jose
Robin A
RA
Felder
D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D011954:Receptors, Dopamine / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D044139:Receptor, Angiotensin, Type 2; D011954:Receptors, Dopamine; D012964:Sodium; D000242:Cyclic AMP; D054648:Protein Phosphatase 2; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP