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gene
1 Laboratory of Kidney and
Electrolyte Metabolism,
Transport
processes along the nephron are regulated in part by hormone
stimulation of adenylyl cyclases mediated by the heterotrimeric G
protein Gs. To assess the role of
this pathway in the regulation of Na-K-2Cl cotransporter abundance in
the renal thick ascending limb (TAL), we studied mice with heterozygous
disruption of the Gnas gene, which
codes for the 
-subunit of Gs.
Outer medullary Gs protein
abundance (as assessed by semiquantitative immunoblotting) and
glucagon-stimulated cAMP production were significantly reduced in the
heterozygous Gs knockout mice
(GSKO) relative to their wild-type (WT) littermates. Furthermore,
Na-K-2Cl cotransporter protein abundance in the outer medulla was
significantly reduced (band density, 48% of WT). In addition, GSKO
mice had a significantly reduced (72% of WT) urinary osmolality in
response to a single injection of
1-deamino-[8-D-arginine]vasopressin
(DDAVP), a vasopressin analog. In contrast, outer
medullary protein expression of the type 3 Na/H exchanger (NHE-3) or
Tamm-Horsfall protein did not differ between the GSKO mice and their WT
littermates. However, abundance of type VI adenylyl cyclase was
markedly decreased in the outer medullas of GSKO mice, suggesting a
novel feed-forward regulatory mechanism. We conclude that
expression of the Na-K-2Cl cotransporter of the TAL is dependent on
Gs-mediated hormone stimulation, most likely due to long-term changes in cellular cAMP levels.
vasopressin; urinary concentrating mechanism; adenosine 3',5'-cyclic monophosphate; sodium-potassium-adenosinetriphosphatase; aquaporins
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