Increased blood pressure and loss of anp-induced natriuresis in mice lacking DARPP-32 gene.
Atrial natriuretic peptide (ANP) is an important regulator of sodium metabolism and indirectly of blood pressure. Evidence has accumulated that ANP regulates sodium metabolism through a cascade of steps involving an increase in the level of cGMP, activation of cGMP-dependent protein kinase (PKG), and inhibition of renal tubular Na+, K+-ATPase activity. One of the major substrates for PKG is DARPP-32. In the present study we observed that ANP does not induce natriuresis in mice that lack DARPP-32. In contrast, there was a 4-fold increase in urinary sodium excretion following ANP administration to wild type mice. ANP as well as Zaprinast, a selective inhibitor of cGMP phosophodiesterase, inhibited renal Na+, K+-ATPase activity in wild type mice but had no such effect in mice lacking DARPP-32. Mean arterial blood pressure, measured in conscious animals, was significantly increased in DARPP-32 deficient mice as compared to wild type mice. The results confirm that DARPP-32 acts as a third messenger in the ANP signaling pathway in renal tissue and suggest an important role of DARPP-32 in the maintenance of normal blood pressure.
Eklöf
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AC
Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
Holtbäck
U
U
Svennilson
J
J
Fienberg
A
A
Greengard
P
P
Aperia
A
A
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology*; D001835:Body Weight / Q000502:physiology; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins; D009929:Organ Size / Q000502:physiology; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics*; D012964:Sodium / Q000652:urine
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D009320:Atrial Natriuretic Factor; D012964:Sodium; D006152:Cyclic GMP