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1 Department of Physiology and Hypertension and Renal Center for Excellence, Tulane University Health Sciences Center School of Medicine, New Orleans, LA, USA
2 Department of Pathology, University of North Carolina, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: kpandey{at}tulane.edu.
The deficiency of Npr1 (genetic determinant of natriuretic peptide receptor-A; NPRA) increases arterial pressures and causes hypertensive heart disease in mice similar to those seen in untreated human hypertensive patients. However, the quantitative role of NPRA in mediating the renal responses to blood volume expansion remains uncertain. To determine the specific contribution of NPRA in mediating the signaling mechanisms responsible for natriuretic and diuretic responses to non-dilutional intravascular expansion, we administered whole blood to anesthetized Npr1 homozygous null mutant (0-copy), wild-type (2-copy), and gene-duplicated (4-copy) mice. In wild-type (2-copy) animals, urine flow (µl/min/g kidney) increased from 4.9 ± 1.0 to 14.4 ± 1.8 and sodium excretion (µEq/min/g kidney) from 1.15 ± 0.22 to 3.11 ± 0.60, associated with a rise in glomerular filtration rate (GFR; ml/min/g kidney) from 0.63 ± 0.03 to 0.82 ± 0.09, and renal plasma flow (RPF; ml/min/g kidney) from 2.96 ± 0.17 to 4.36 ± 0.41, while arterial pressure did not significantly increase. After volume expansion, 0-copy mice showed significantly lesser increases in urine flow (p<0.001) and sodium excretory (p<0.001) responses even though the increases in arterial pressures were greater (p<0.001), as compared with 2-copy mice. The 4-copy mice showed augmented responses in urine flow (p<0.01) and sodium excretion (p<0.001) along with rises in both GFR (p<0.01) and RPF (p<0.01) as compared with 2-copy wild-type mice. These results establish that NPRA activation is the predominant mechanism mediating the natriuretic, diuretic, and renal hemodynamic responses to acute blood volume expansion.
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