Role of cAMP-phosphodiesterase isozymes in pathogenesis of murine nephrogenic diabetes insipidus.
To test the hypothesis that rapid adenosine 3',5'-cyclic monophosphate (cAMP) catabolism via cyclic 3',5'-nucleotide phosphodiesterase (PDE) is a cause of the unresponsiveness to vasopressin (VP) in mice with hereditary nephrogenic diabetes insipidus (NDI), we investigated properties of PDEs and other aspects of the VP-dependent cAMP-signaling system in segments of collecting ducts [inner medullary (IMCD), cortical (CCD), and outer medullary (OMCD) ducts] microdissected from control mice and mice with NDI. The activity of cAMP-PDE, but not of cGMP-PDE, was markedly higher in IMCD (+109%), and to a lesser degree in OMCD (+41%) and CCD (+27%), of NDI mice than in normal controls. The cAMP-PDE in IMCD of NDI mice was more sensitive to inhibition by the PDE isozyme-specific inhibitors rolipram and cilostamide, but not by 3-isobutyl-1-methylxanthine, than was the cAMP-PDE in controls. Levels of cAMP in intact IMCD and CCD from NDI mice completely failed to increase in response to 10(-6) M VP. Incubation with rolipram alone, but not with cilostamide alone, restored VP-dependent cAMP accumulation in IMCD of NDI mice to the levels found in control mice; addition of cilostamide further enhanced the effect of rolipram. Analogous (but quantitatively lesser) anomalies of the VP-dependent cAMP system, including the effects of PDE inhibitors, were observed also in CCD of NDI mice. However, the activity of VP-stimulated adenylate cyclase assayed in permeabilized IMCD did not differ in NDI and control mice. These results indicate that anomalously high activities of low-Km cAMP-PDE isozymes account for the failure of collecting ducts of NDI mice to increase cAMP levels in response in VP.(ABSTRACT TRUNCATED AT 250 WORDS)
Homma
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S
Department of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Gapstur
S M
SM
Coffey
A
A
Valtin
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H
Dousa
T P
TP
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism / Q000502:physiology*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003919:Diabetes Insipidus / Q000209:etiology* / Q000235:genetics; D005260:Female; D006868:Hydrolysis; D007527:Isoenzymes; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009399:Nephrons / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases