Function of cGMP-dependent protein kinase II in volume load-induced diuresis.
Atrial natriuretic peptide (ANP)/cGMPs cause diuresis and natriuresis. Their downstream effectors beyond cGMP remain unclear. To elucidate a probable function of cGMP-dependent protein kinase II (cGKII), we investigated renal parameters in different conditions (basal, salt diets, starving, water load) using a genetically modified mouse model (cGKII-KO), but did not detect any striking differences between WT and cGKII-KO. Thus, cGKII is proposed to play only a marginal role in the adjustment of renal concentration ability to varying salt loads without water restriction or starving conditions. When WT mice were subjected to a volume load (performed by application of a 10-mM glucose solution (3% of BW) via feeding needle), they exhibited a potent diuresis. In contrast, urine volume was decreased significantly in cGKII-KO. We showed that AQP2 plasma membrane (PM) abundance was reduced for about 50% in WT upon volume load, therefore, this might be a main cause for the enhanced diuresis. In contrast, cGKII-KO mice almost completely failed to decrease AQP2-PM distribution. This significant difference between both genotypes is not induced by an altered p-Ser256-AQP2 phosphorylation, as phosphorylation at this site decreases similarly in WT and KO. Furthermore, sodium excretion was lowered in cGKII-KO mice during volume load. In summary, cGKII is only involved to a minor extent in the regulation of basal renal concentration ability. By contrast, cGKII-KO mice are not able to handle an acute volume load. Our results suggest that membrane insertion of AQP2 is inhibited by cGMP/cGKII.
Pharmacology and Toxicology, Institute of Pharmacy, University of Regensburg, Universitätsstr 31, 93053, Regensburg, Germany.
Andrea
A
Schramm
Elisabeth
E
Schinner
Johannes P
JP
Huettner
Frieder
F
Kees
Philipp
P
Tauber
Franz
F
Hofmann
Jens
J
Schlossmann
D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D062967:Cyclic GMP-Dependent Protein Kinase Type II / Q000235:genetics / Q000378:metabolism*; D004231:Diuresis; D005947:Glucose / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D010766:Phosphorylation; D021381:Protein Transport; D065667:Renal Elimination; D012964:Sodium / Q000378:metabolism
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D012964:Sodium; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D005947:Glucose