Impaired water reabsorption in mice deficient in the type VI adenylyl cyclase (AC6).

Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
FEBS letters (Impact Factor: 3.54). 07/2010; 584(13):2883-90. DOI: 10.1016/j.febslet.2010.05.004
Source: PubMed

ABSTRACT Adenylyl cyclase (AC) type VI (AC6) is a calcium-inhibitable enzyme which produces cAMP upon stimulation. Herein, we characterized the specific role of AC6 in the kidneys using two AC6-knockout mouse lines. Immunohistochemical staining revealed that AC6 exists in the tubular parts of the nephron and collecting duct. Activities of AC evoked by forskolin or a selective agonist of the V2 vasopressin receptor were lower in the kidneys of AC6-null mice compared to those of wildtype mice. Results of a metabolic cage assay and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) showed for the first time that AC6 plays a critical role in regulating water homeostasis.

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    ABSTRACT: Adenylyl cyclase (AC)‐stimulated cAMP is a key mediator of collecting duct (CD) Na and water transport. AC isoforms 3, 4, and 6 are expressed in the CD. Our group demonstrated that AC6, but not AC3, is involved in regulating CD Na and water transport. However, the role of AC4 in such regulation remains unknown. Therefore, we generated mice with loxP‐flanked critical exons in the Adcy4 gene and bred with mice expressing the aquaporin‐2/Cre recombinase transgene to yield CD principal cell‐specific knockout of AC4 (CD AC4 KO). Isolated inner medullary CD showed 100% genomic target gene recombination in CD AC4 KO mice, while microdissected cortical CD and renal papillary AC4 mRNA was significantly reduced in CD AC4 KO mice. CD AC4 KO had no effect on vasopressin (AVP)‐stimulated cAMP generation in the inner medulla. Water intake, urine volume, and urine osmolality were similar between CD AC4 KO and control mice during normal or restricted water intake. Sodium intake, urinary Na excretion, and blood pressure on a normal‐, high‐, or low‐Na diet were not affected by CD AC4 KO. Moreover, there were no differences in plasma AVP or plasma renin concentration between CD AC4 KO and control mice. In summary, these data suggest that CD AC4 does not play a role in the physiologic regulation of CD Na and water handling.
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    ABSTRACT: Visceral functions are regulated by a basal sympathetic nerve discharge (SND), also known as 'sympathetic tone'. We demonstrate herein that AC6 existed in tyrosine hydroxylase-positive rostral ventrolateral medulla neurons in the brainstem. Adenylyl cyclase (AC) assays showed lower basal and pituitary adenylate cyclase-activating peptide-evoked AC activities in the brainstem of AC6-null mice, indicating that AC6 is a prominent AC isozyme in the brainstem. Furthermore, two independent lines of AC6-null mice exhibited a much higher SND, recorded from splanchnic sympathetic nerves of neonatal brainstem-spinal cord preparations, than wildtype mice. An assay of urine noradrenaline confirmed this observation. Collectively, AC6 plays a critical role in the regulation of sympathetic tone.
    Experimental Neurology 05/2013; · 4.65 Impact Factor
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    ABSTRACT: Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.
    Journal of the American Society of Nephrology 12/2012; · 8.99 Impact Factor

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