A genetic model defines the importance of the atrial natriuretic peptide receptor (guanylyl cyclase-A) in the regulation of kidney function

Abstract

Disruption of the atrial natriuretic peptide (ANP) receptor [guanylyl cyclase-A (GC-A)] gene yields mice with a salt-resistant form of hypertension, raising fundamental questions on the role of ANP in acute regulation of the kidney. Here, we show that water intake, food consumption, stool weight, urine volume, and sodium excretion are not significantly different between wild-type and GC-A null mice on standard rodent chow (0.7% NaCl) or a high-salt diet (8% NaCl). In conscious mice with an indwelling catheter, the infusion of a physiological saline solution containing 4% BSA resulted in a marked natriuresis͞diuresis in wild-type mice but no response in GC-A null animals. When physiological saline was given by gavage, however, the kidney response of wild-type and null mice was equivalent, raising the possibility that the gastrointestinal tract can directly regulate kidney function. However, administration of 0.9% saline through an intraperitoneal route also resulted in equal kidney responses in wild-type and null mice. When 0.9% NaCl lacking protein was infused i.v., wild-type and null mice both responded at the kidney level. Thus, GC-A appears dispensable for regulation of sodium͞water excretion in response to changes in dietary sodium concentration, but likely becomes critical in volume expansions where the isooncotic pressure remains constant, such as head-out immersion or the initial and correctable stages of congestive heart failure.

Sgk1 Mediates Osmotic Induction of NPR-A Gene in Rat Inner Medullary Collecting Duct Cells

“…In the kidney, it appears to be exclusively NPR-A that signals the natriuretic activity of atrial natriuretic peptide. 3 The medullary interstitium that bathes the basolateral surface of the inner medullary collecting duct (IMCD) cell is the only tissue in the body that is almost continuously exposed to a hyperosmotic environment. This increase in tonicity has the potential to control a variety of metabolic processes in these cells, including those responsible for regulating cellular volume.…”

A gene therapy approach for long-term normalization of blood pressure in hypertensive mice by ANP-secreting human skin grafts

“…4A). These levels are within the low-dose ANP infusion ranges (12-180 pg/mL) that previously were reported to produce an effective and prolonged reduction in blood pressure in patients (24) and are within reported ranges (30-100 pg/mL) of murine ANP levels (25)(26)(27). Serial measurement of human ANP levels in individual mice, analyzed at 4 and 7 months after grafting of different HSE combinations (Fig.…”

The Regulation and Physiological Roles of the Guanylyl Cyclase Receptors.

“…5). However, the essential importance appears restricted to conditions of isooncotic volume expansion [179]. On a low-salt diet (0.008% NaCI) GC-A null mice show 1.5-fold higher plasma aldosterone concentrations than wild-type mice, but a high-salt diet (8% NaCI) reduces aldosterone concentrations to under the detectable limit in both genotypes [168].…”

“…Genetic titration of the GC-A gene decreases systolic blood pressure as a function of GC-A gene copy number; this also suggests an important role of GC-A in blood pressure regulation [177]. Acute volume expansion by intravenous isooncotic solution infusion, which leads to an increase of plasma ANP concentrations, does not cause an increase in water and sodium excretion in GC-A null mice, while it causes significant elevation in wild-type mice [178,179]. Intravenous ANP infusion also has no diuretic and natriuretic effects in GC-A null mice [178].…”

“…GC-A null mice can increase water and sodium excretion indistinguishably from wild-type mice in response to volume expansion through the gut [179], raising the possibility that a water-electrolyte regulatory system independent from the ANP/GC-A system exists in the gut. GC-C null mice, however, do not show blood pressure elevations [170].…”