Renal hyporesponsiveness to atrial natriuretic peptide in congestive heart failure results from reduced atrial natriuretic peptide receptor concentrations.
Atrial natriuretic peptide (ANP) and B-type natriuretic peptide decrease blood pressure and cardiac hypertrophy by activating natriuretic peptide receptor A (NPR-A), a transmembrane guanylyl cyclase also known as guanylyl cyclase A. Inactivation of NPR-A is a potential mechanism for the renal hyporesponsiveness observed in congestive heart failure (CHF) but direct data supporting this hypothesis are lacking. We examined whether NPR-A activity was reduced in CHF, and if so, by what mechanism. In two separate trials, CHF was induced in mice by 8-wk transverse aortic constriction. Sham controls underwent surgery without constriction. The constricted animals developed severe heart failure as indicated by increased heart weight, increased left ventricular end diastolic and systolic diameters, and decreased left ventricular ejection fractions. Kidney membranes were assayed for guanylyl cyclase activity or used to purify NPR-A by sequential immunoprecipitation/SDS-PAGE. Maximal ANP-dependent guanylyl cyclase activities were reduced by 44 or 43% in kidney membranes from CHF animals in two independent trials. Basal cyclase activities were also reduced by 31% in the second trial. The amount of phosphorylated NPR-A was reduced by 25 or 24% in kidney membranes from CHF animals as well. SYPRO Ruby staining suggested that NPR-A protein levels were similar between treatments in the first trial. However, more accurate estimates of NPR-A protein levels by immunoprecipitation/Western analysis in the second trial indicated that NPR-A protein was reduced by 30%. We conclude that reduced NPR-A protein levels, not receptor dephosphorylation, explain the renal hyporesponsiveness to natriuretic peptides in CHF.
Bryan
Paula M
PM
Departments of Biochemistry, Molecular Biology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Xu
Xin
X
Dickey
Deborah M
DM
Chen
Yingjie
Y
Potter
Lincoln R
LR
D000818:Animals; D001011:Aorta; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D015153:Blotting, Western; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000209:etiology; D003251:Constriction, Pathologic; D004452:Echocardiography; D006162:Guanylate Cyclase / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D047468:Immunoprecipitation; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds; D009994:Osmolar Concentration; D010766:Phosphorylation; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency* / Q000378:metabolism; D013194:Staining and Labeling
D009942:Organometallic Compounds; C515601:Sypro Ruby; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor