Cellular Action of Antidiuretic Hormone in Mice with Inherited Vasopressin-Resistant Urinary Concentrating Defects

Abstract

A B S T R A C T Previous workand decreased to a lesser extent in DI +/+ nonsevere animals. A significant correlation was found between the activity of adenylate cyclase maximally stimulated by AVP in a given genotype, and the urine osmolality in the same animals. There were no significant differences in maximal stimulation of renal medullary adenylate cyclase in control experiments: not when stimulated nonspecifically by sodium fluoride, nor when stimulated by AVP in tissues from rats with induced water diuresis as compared to antidiuretic rats. Nor were there significant differences between VII +/+ and DI +/+ severe mice in the activity of renal cortical adenylate Preliminary reports of this work have appeared in abstract form:

Cellular Action of Vasopressin in Medullary Tubules of Mice with Hereditary Nephrogenic Diabetes Insipidus

“…As in our previous study (4), the so-called DI +/+ severe strain of mice with fully expressed NDI (2-4) were compared with the the VII +/+ strain, which have normal concentrating ability and serve as controls. These two strains are subsequently referred to in the text as "NDI mice" and "control mice," respectively.…”

“…One animal model that phenotypically closely resembles human hereditary nephrogenic diabetes insipidus (NDI)l is a strain of mouse (so-called DI +/+ severe) with an inherited, vasopressin (VP)-resistant urinary concentrating defect (1)(2)(3)(4). Because administration of VP to NDI mice fails to increase osmolality of hypotonic urine (2, 3), these functional features indicate that collecting tubules failed to increase water permeability in response to the hormone.…”

“…Because administration of VP to NDI mice fails to increase osmolality of hypotonic urine (2,3), these functional features indicate that collecting tubules failed to increase water permeability in response to the hormone. It is well established that the hydroosmotic effect of VP in collecting tubules (5)(6)(7)(8) is mediated by adenosine 3',5'-cyclic monophosphate (cAMP) (5-7), and we have previously investigated the possibility that unresponsiveness to VP in NDI mice might be the result of a defect in VP-dependent cAMP metabolism (4,9,10).…”

“…In our previous studies (4), we investigated several known (or hypothetical) biochemical components involved in the cellular action of VP in a cell-free system (4). In washed membrane fractions prepared from the renal medulla (outer and inner medulla taken together), stimulation of adenylate cyclase by VP was lower in preparations from NDI mice than from control mice with an intact urinary concentrating mechanism (4).…”

“…In washed membrane fractions prepared from the renal medulla (outer and inner medulla taken together), stimulation of adenylate cyclase by VP was lower in preparations from NDI mice than from control mice with an intact urinary concentrating mechanism (4). Because the responsiveness of renal medullary adenylate cyclase to VP in NDI mice was diminished but not absent, it remained an open question whether such a partial deficiency could be the cause of complete ftunctional unresponsiveness to VP (9,10).…”