Soluble (pro)renin receptor as a potential therapy for diabetes insipidus.

The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs) on the basolateral membrane of principal cells of the collecting duct (CD) to regulate fluid permeability. The VP-evoked endocrine pathway is essential in determining urine concentrating capability. For example, a defect in any component of the VP signaling pathway can result in polyuria, polydipsia, and hypotonic urine, collectively termed diabetes insipidus (DI). A lack of VP production precipitates central diabetes insipidus (CDI), which can be managed effectively by VP supplementation. A majority of cases of nephrogenic diabetes insipidus (NDI) result from V2R mutations that impair receptor sensitivity. No specific therapy is currently available for management of NDI. Evidence is evolving that (pro)renin receptor (PRR), a newly identified member of the renin-angiotensin system, is capable of regulating VP production and action. As such, PRR should be considered strongly as a therapeutic target for treating CDI and NDI. The current review will summarize recent advances in understanding the physiology of renal and central PRR as it relates to the two types of DI.

The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report.

BACKGROUND: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known. CASE PRESENTATION: A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner. CONCLUSION: Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.

A urine-concentrating defect in 11ß-hydroxysteroid dehydrogenase type 2 null mice.

In aldosterone target tissues, 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2(-/-) mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2(-/-) mice and controls. Hsd11b2(-/-) mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (∼2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2(-/-) mice (>6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2(-/-) mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2(-/-) mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin.

Mineralocorticoid regulation of cyclooxygenase-2 expression in rat renal medulla.

The renal inner medulla and its distal one-third, the papilla, are major sites of prostanoid synthesis involved in water and electrolyte homeostasis. These sites contain variable levels of cyclooxygenase (COX)-2, a key prostaglandin synthase enzyme that is sensitive to adrenal steroids. Immunoreactive renal medullary COX-2, restricted to interstitial cells in control adult rats, shows a gradient of intense staining at the tip of the papilla that gradually diminishes to undetectable levels in the proximal inner medulla. We used adrenalectomy (ADX) and steroid replacement to investigate the effects of steroids on papillary COX-2. Immunoblots demonstrate that papillary COX-2 was reduced by one-half after 2 wk ADX; glucocorticoid replacement ameliorated the decline but not to control levels. Mineralocorticoid (deoxycorticosterone acetate; DOCA) replacement stimulated papillary COX-2 more than fivefold over control; both the intensity of immunostaining and the numbers of COX-2-positive cells in the inner medulla increased. Similar stimulation of papillary COX-2 resulted from DOCA treatment of normal control rats, but the response was blunted in rats fed a low-salt diet and absent in Brattleboro rats. DOCA treatment of mouse renal medullary interstitial cells in culture had no effect, but increased tonicity of the culture medium with NaCl caused strong upregulation of COX-2. Urea, a permeant molecule, had no effect. Together, these results suggest that mineralocorticoids lead to upregulation of COX-2 in rat renal medulla by indirect pathways, probably involving induced electrolyte hypertonicity in the interstitial fluid.

La vasopresinasa, una enzima con repercusiones clínicas / Vasopresinase, an enzyme with clinical repercussions

La vasopresinasa es una aminopeptidasa, enzima producida por la placenta. Su actividad se ha visto implicada en el desencadenamiento de un tipo de diabetes insípida de la gestante (caso que presentamos), en algunos casos de preeclampsia e hígado graso asociados a la anterior e incluso en el mantenimiento del embarazo (participando en el catabolismo enzimático de la oxitocina) y, por tanto, previniendo el parto prematuro. De todos modos, su verdadera función es todavía un enigma (AU)

Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase.

Uricase-deficient mice develop uric acid nephropathy, with high mortality rates before weaning. Urate excretion was quantitated and renal function was better defined in this study, to facilitate the use of these mice as a model for evaluating poly(ethylene glycol)-modified recombinant mammalian uricases (PEG-uricase) as a potential therapy for gout and uric acid nephropathy. The uric acid/creatinine ratio in the urine of uricase-deficient mice ranges from 10 to >30; on a weight basis, these mice excrete 20- to 40-fold more urate than do human subjects. These mice consistently develop a severe defect in renal concentrating ability, resulting in an approximately sixfold greater urine volume and a fivefold greater fluid requirement, compared with normal mice. This nephrogenic diabetes insipidus leads to dehydration and death of nursing mice but, with adequate water replacement, high urine flow protects adults from progressive renal damage. Treatment of uricase-deficient mice with PEG-uricase markedly reduced urate levels and, when initiated before weaning, preserved the renal architecture (as evaluated by magnetic resonance micros-copy) and prevented the loss of renal concentrating function. PEG-uricase was far more effective and less immunogenic than unmodified uricase. Retention of uricase in most mammals and its loss in humans and some other primates may reflect the evolution of renal function under different environmental conditions. PEG-uricase could provide an effective therapy for uric acid nephropathy and refractory gout in human patients.

Differential clinical courses of pregnancies complicated by diabetes insipidus which does, or does not, pre-date the pregnancy.

We present six cases of diabetes insipidus (DI) complicating pregnancy. In three cases, DI was manifested during pregnancy and required the administration of desmopressin acetate (1-desamino-8-D-arginine vasopressin, DDAVP). All these cases exhibited abnormal laboratory data such as an elevation of liver enzymes or a decrease in serum antithrombin III. The remaining three cases had suffered from DI before pregnancy which was well controlled on DDAVP. The clinical courses of these pregnancies were all uneventful subsequent to therapy. If DI is first recognized during pregnancy, attention should be paid to the possibility of abnormal liver function and eclampsia.

Constitutive nitric oxide synthase in hypothalami of normal and hereditary diabetes insipidus rats and mice: role of nitric oxide in osmotic regulation and its mechanism.

Constitutive nitric oxide synthase (cNOS) was immunolocalized to study its role in osmotic regulation. Immunoreactivity was observed in all major hypothalamic osmoregulatory structures, the organum vasculosum laminae terminalis, subfornical organ, median preoptic nucleus, and supraoptic and paraventricular nuclei. These nuclei were compared in normal Long-Evans rats and homozygous Brattleboro rats with hereditary hypothalamic diabetes insipidus and in normal mice and mice with hereditary nephrogenic diabetes insipidus. About 50% of supraoptic neurons in Long-Evans rats and 90% in Brattleboro rats were cNOS immunopositive; a qualitatively similar difference occurred in the paraventricular nucleus. Mice with hereditary nephrogenic diabetes insipidus also showed a greater proportion of cNOS-positive supraoptic neurons (50%) than normal mice (20%). However, the number of cNOS-positive cells in the organum vasculosum laminae terminalis, subfornical organ, and median preoptic nucleus dis not differ significantly between diabetic and normal animals. The similar changes in cNOS in two mutant strains in which the only common feature is chronic osmotic stimulation shows that differences in vasopressin and oxytocin are not involved in the regulation of cNOS. The results suggest strongly that cNOS is involved in long term modulation of the hypothalamo-neurohypophysial system and, hence, body water and electrolyte homeostasis, and that cNOS is itself regulated by body osmotic status.

Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms.

In the last few years there has been a veritable explosion of knowledge about cyclic nucleotide phosphodiesterases. In particular, the accumulating data showing that there are a large number of different phosphodiesterase isozymes have triggered an equally large increase in interest about these enzymes. At least seven different gene families of cyclic nucleotide phosphodiesterase are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of phosphodiesterases. Particular emphasis is placed on new information obtained in the last few years about how differential expression and regulation of individual phosphodiesterase isozymes relate to their function(s) in the body. A substantial discussion of the currently accepted nomenclature is also included. Finally, a brief discussion is included about how the differences among distinct phosphodiesterase isozymes are beginning to be used as the basis for developing therapeutic agents.

Cathepsin L immunoreactivity in the hypothalamus of normal, streptozotocin-diabetic and vasopressin-deficient Brattleboro rats.

The immunolocalization of cathepsin L in the hypothalamus of normal rats was compared with the distribution of the enzyme in streptozotocin-treated animals and in vasopressin-deficient rats (Brattleboro strain). In rats with a normal metabolic status the neurons of magnocellular nucl. supraopticus and paraventricularis stood out by intense immunostaining for cathepsin L. In rats suffering from an experimentally induced diabetes mellitus and in homozygous Brattleboro rats we observed a strong reduction in enzyme immunoreactivity in these nuclei. Since cathepsin L is capable of splitting certain hypothalamic neuropeptides that are changed in diabetic animals, a role of the enzyme in the metabolism of these peptides is imaginable. Decrease in immunoreactive cathepsin L in vasopressin-deficient rats points to a possible involvement of the enzyme in the control of fluid homeostasis.

Processing endopeptidase deficiency in neurohypophysial secretory granules of the diabetes insipidus (Brattleboro) rat.

The homozygote Brattleboro rat exhibits a hereditary diabetes insipidus due to a deficiency of vasopressin, the antidiuretic hormone. It has previously been shown that in this animal a single nucleotide deletion in the provasopressin gene leads to a mutant precursor with a C-terminal amino acid sequence different from that of the wild-type. However the N-terminal region including the hormone moiety, the processing signal as well as the first two-thirds of the neurophysin is entirely preserved and absence of maturation has to be explained by an additional cause. We show here that the neurohypophysis of the homozygote Brattleboro rat, in contrast to the adenohypophysis, displays a significant decrease in the Lys-Arg processing endopeptidase activity when compared to the heterozygote or the wild-type Wistar. It is suggested that hypothalamic vasopressinergic neurons of the homozygote Brattleboro rat display a deficiency in the processing enzyme in contrast to the oxytocinergic neurons in which processing of prooxytocin is normal.

Cerebrospinal fluid placental alkaline phosphatase in the intracranial germinomas: results of enzyme antigen immunoassay.

The authors investigated the placental alkaline phosphatase (PALP) activity in cerebrospinal fluid (CSF) by enzyme-antigen immunoassay using polyclonal antibody as a marker for intracranial germinomas in 17 patients with germ cell tumors and 20 with other disorders. The detection limit of PALP activity was 0.072 optical density units equivalent to 5.9 ng/ml. Five of nine germinomas demonstrated high CSF PALP activities before treatment. These high PALP activities became undetectable following radiation therapy. The other tumors were small or had no CSF contact. CSF PALP activity is a useful tumor marker for pure germinomas.

High activity of low-Michaelis-Menten constant 3', 5'-cyclic adenosine monophosphate-phosphodiesterase isozymes in renal inner medulla of mice with hereditary nephrogenic diabetes insipidus.

Our previous studies on microdissected kidney tubule segments indicate that the failure of vasopressin (VP) to increase cAMP content in collecting ducts of mice with hereditary nephrogenic diabetes insipidus (NDI mice) is due to abnormally rapid cAMP catabolism via cyclic-3',5'-nucleotide phosphodiesterases (PDE). Furthermore, the VP-stimulated cAMP accumulation can be restored by addition of PDE isozyme-specific inhibitors. To elucidate the biochemical basis of the NDI syndrome, we analyzed PDE activities in extracts from inner medullary tissues of NDI mice and from control mice separated with the use of ionex fast protein liquid chromatography on a Mono-Q column. In extracts of inner medullary tissues from either control or NDI mice, the low Michaelis-Menten constant (Km) cAMP-PDE activity specific for cAMP as a substrate (cAMP-PDE) was eluted from a Mono-Q column with linear sodium acetate gradient as peak 3 at Na-acetate concentration (0.75-0.93 M) and was well separated from fractions containing the Ca(2+)-calmodulin sensitive PDE. The cAMP-PDE activity in peak 3 was significantly higher in NDI mice (greater than delta + 100%) than in controls. The sensitivity to effect of cAMP-PDE isozyme-specific inhibitors, rolipram and cilostamide, indicates that peak 3 consists predominantly (approximately 75%) of the rolipram-sensitive PDE-IV isozyme and a minor portion (approximately 25%) of cilostamide-sensitive PDE-III isozyme in both control and NDI mice. Higher activity of PDE-IV in NDI mice was due to 2.4 times higher apparent maximum velocity compared to controls, whereas the apparent Km for cAMP was not different. Our results show that low Km cAMP-PDE activities, predominantly PDE-IV, are higher in inner medulla of NDI mice. We suggest that the higher activity of PDE-IV, and to a lesser degree perhaps also PDE-III, accounts for rapid cAMP hydrolysis, which prevents the increase of cAMP generated in the response to VP in collecting ducts of NDI mice.

Arginine vasopressin gene regulation in the homozygous Brattleboro rat.

The Brattleboro rat, which has an autosomally recessive form of diabetes insipidus, has been reported to have a marked defect in the regulation of arginine vasopressin (AVP) gene expression. However, it is not known whether this is a primary genetic defect or occurs secondary to the urinary water losses which occur in the absence of circulating AVP in the Brattleboro rat. This present study was therefore undertaken to study AVP gene regulation in the Brattleboro rat after chronic AVP treatment by osmotic minipump for 2 wk. In Brattleboro rats without AVP treatment, neither urinary osmolality (Uosm) nor hypothalamic AVP mRNA was significantly changed after 24 h of fluid deprivation (Uosm, 413 +/- 33 to 588 +/- 44, NS; AVP mRNA, 39.33 +/- 2.95 to 46.39 +/- 2.71 pg/micrograms total RNA, NS). In contrast, when Brattleboro rats were treated with AVP for 2 wk, the regulation of AVP gene occurred in response to 24 h of fluid deprivation. In these studies, hypothalamic AVP mRNA was significantly increased compared with the Brattleboro rats still receiving AVP with free access of water (28.9 +/- 3.5 vs. 65.0 +/- 3.3 pg/micrograms total RNA, P less than 0.001). Further studies in Long-Evans rats demonstrate a similar response to a comparable degree of fluid deprivation as Uosm and AVP mRNA were significantly increased after 72 h of fluid deprivation (Uosm, 1,505 +/- 186 to 5,460 +/- 560 mosmol/kg, P less than 0.001; AVP mRNA, 31.7 +/- 3.9 to 77.5 +/- 4.6 pg/micrograms total RNA, P less than 0.001). These results indicate that AVP-replaced homozygous Brattleboro rats can regulate AVP gene expression normally in response to fluid deprivation. This finding indicates that the defect in AVP gene regulation in the Brattleboro rat not receiving AVP replacement is a secondary phenomenon rather than a primary genetic defect.

Transient diabetes insipidus of pregnancy.

Transient diabetes insipidus (DI) is a disease of late pregnancy, that has been reported with increasing frequency. Although initially thought to be nephrogenic, the etiology of this syndrome is most likely excess vasopressinase activity. The disease is associated with preeclampsia with liver involvement. Infants of mothers with the syndrome are predominantly male. Management may be with deamino D arginine vasopressin (dDAVP) during gestation and postpartum since vasopressinase does not break down dDAVP. The copious urine output may disguise preeclampsia. Fluid restriction should be avoided as it will lead to dehydration and hemoconcentration.

Developmental and physiological regulation of aldose reductase mRNA expression in renal medulla.

Aldose reductase (AR), an enzyme that catalyzes the conversion of glucose to sorbitol, has been implicated in the pathogenesis of many of the complications of diabetes mellitus, but its normal physiological function in various tissues remains uncertain. It has been suggested that in the kidney, sorbitol production may be an important cellular protection against medullary intersitital hypertonicity. Using in situ and Northern hybridization analyses, we found that at the time of birth, AR mRNA expression in the kidney was very low and seen only in the papilla. By 12 days of age, at about the time a corticopapillary osmotic gradient and the capacity for urinary concentration have developed, a striking increase in renal AR mRNA levels was seen. It was confined to the inner medulla and was characterized by a dramatic gradient of expression paralleling the corticopapillary osmotic gradient. Levels of expression were somewhat lower in adults, but showed the same inner medullary boundary and gradient. Under these hybridization and exposure conditions, no AR transcripts were detected in the outer medulla or cortex. Homozygous Brattleboro rats with congenital diabetes insipidus have relatively dilute corticopapillary osmotic gradients, and their level of medullary AR mRNA was significantly lower than that of controls. Conversely, normal rats made hyperosmotic and, hence, antidiuretic by salt loading showed a large increase in medullary AR mRNA. These changes in renal medullary AR gene expression in correlation with changes in medullary tonicity support the hypothesis that renal AR plays a role in cellular adaption to osmotic stress and suggest that local medullary osmolarity may regulate the level of AR gene expression.

Developmental and physiological pattern of aldose reductase mRNA expression in lens and retina.

Aldose reductase (AR), an enzyme which converts glucose to sorbitol, has been implicated in the pathogenesis of diabetic cataracts and retinopathy. The normal physiological role of this enzyme in ocular tissue, however, remains unclear. In a developmental study in the rat using in situ and Northern hybridization analyses, we have found that there is a high level of AR mRNA expression in optic cup and lens as early as embryonic day 13. Serial sections through whole embryos at this stage showed that the eye was the only site of AR mRNA hybridization. Levels of AR mRNA declined in the retina as differentiation proceeded and were very sparse there postnatally. As lens development progressed, epithelial AR mRNA levels remained high, especially in the germinative zone, which is the source of the cells that will become lens fibers, and in the bow region, where these cells undergo a dramatic morphogenetic differentiation into lens fibers. AR mRNA was undetectable in terminally differentiated lens fibers. Since it has been suggested that AR-catalyzed sorbitol production could be an osmoprotective device of lens epithelium during systemic hyperosmolar stress, AR mRNA levels from dehydrated hyperosmolar rats were compared with euvolemic control values, and no difference was found. In summary, AR appears to be of particular importance in the development of the eye, with its retinal role receding relative to lens as differentiation is completed. A continued high level of expression in lens epithelium in adulthood may be explained by the fact that lens tissue, unlike retina, normally continues to proliferate and differentiate after birth. The temporal and spatial pattern of distribution of AR mRNA is strongly suggestive of a role for this enzyme in lens fiber morphogenesis.