Induction of intramembranous particle clusters in mice with nephrogenic diabetes insipidus

Abstract

In mice with hereditary nephrogenic diabetes insipidus (NDI), the inability of vasopressin to increase hydraulic water permeability is reflected in a lack of intramembranous particle (IMP) clusters in apical membranes of inner medullary collecting ducts. The lack arises from anomalously high activity of one or two isozymes of adenosine 3',5'-cyclic monophosphate-phosphodiesterase (cAMP-PDE). We asked whether inhibition of these isozymes with rolipram and cilostamide would raise not only the tissue content of cAMP but also and simultaneously restore IMP clusters. Inner medullary collecting ducts from NDI mice were incubated in vitro. Tissue content of cAMP (fmol of cAMP per bundle) and number of IMP clusters (per 100 microns 2 of principal cell apical membrane) were, respectively: control, 44.8 +/- 13.0 and 4.16 +/- 1.49; arginine vasopressin (AVP), 31.7 +/- 8.0 and 3.98 +/- 1.56; rolipram and cilostamide, 109.7 +/- 21.0 and 58.09 +/- 15.74; and AVP plus rolipram and cilostamide, 305.7 +/- 75 and 48.63 +/- 11.03 (with the last four values showing significant difference from control and AVP only, respectively). In addition, treating NDI mice with rolipram and cilostamide in vivo reduced their high fluid turnover. We conclude that failure by AVP to increase cAMP in cells of collecting ducts, which results from anomalously high activity of one or two specific isozymes of cAMP-PDE, is the major or sole cause for the excretion of hypotonic urine in NDI mice (DI +/+ Severe strain).

Stimulation of AQP2 membrane insertion in renal epithelial cells in vitro and in vivo by the cGMP phosphodiesterase inhibitor sildenafil citrate (Viagra)

“…Most of the attempts to resolve this problem using alternative methods of increasing intracellular cAMP, including recent work using oxytocin, have not been successful (27). In a strain of mice with NDI that is due to overexpression of rolipram-sensitive cAMP PDE4 in collecting duct principal cells, administration of rolipram to isolated collecting ducts resulted in morphological changes (seen by freeze-fracture electron microscopy) consistent with an increase in apical membrane water channels (10). These mice also have lower levels of AQP2 protein than normal mice, consistent with the fact that in vivo regulation of AQP2 expression by vasopressin is mediated by cAMP (18).…”

Antidiuretic hormone resistance in the neonatal cortical collecting tubule is mediated in part by elevated phosphodiesterase activity

“…This would limit the amount of cAMP generated when ADH binds to the tubule and blunts the water permeability response to ADH. When these mice were treated with a phosphodiesterase inhibitor, their urinary osmolality increased (8). Another condition that is associated with increased phosphodiesterase activity is glucocorticoid deficiency (15,35).…”

Aquaporins in the Kidney: From Molecules to Medicine

“…Evidence for this comes from experiments with DI ϩ/ϩ severe mice, a strain with an activating mutation of cAMP phosphodiesterase. This means that there is no rise in cytosolic cAMP in response to vasopressin (40), resulting in a failure of the acute antidiuretic response to vasopressin. These mice show severely reduced levels of AQP2, suggesting that cAMP acts as the second messenger for vasopressin stimulation of AQP2 expression as well as shuttling (78).…”