Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus

Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.     

A Low Affinity Vasopressin V2-Receptor in Inherited Nephrogenic Diabetes Insipidus

Abstract

Congenital nephrogenic diabetes insipidus (NDI) is an X-linked inherited disorder characterized by renal resistance to the antidiuretic hormonal action of vasopressin. This study describes the molecular basis of nephrogenic diabetes insipidus in a dog family. Kidney membranes prepared from NDI-affected male huskies were examined for vasopressin binding and response. Compared to membranes from unaffected canines, those from the kidney inner medulla of NDI-dogs possessed normal V₂-receptor numbers, but with 10–fold lower affinity for [Arg⁸] vasopressin (AVP). Adenylate cyclase stimulation by AVP in contrast to that by forskolin or GTP-analogues was similarly reduced in a dose responsive manner. The NDI-affected dogs showed antidiuretic responses to very high doses of V₂–specific agonists, consistent with their possessing V₂–receptors of lower affinity. Prolonged treatment with V₂–agonists, 1–deamino [D-Arg⁸] VP (dDAVP) and 1–deamino [Va]⁴, Sar⁷] AVP (dVSAVP), rendered the NDI-affected dogs near normal in terms of water intake and urine osmolality.     

DDAVP in Treatment of Vasopressin-Sensitive Diabetes Insipidus

In 11 patients with vasopressin-sensitive diabetes insipidus the effectiveness of the vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP) for controlling diabetes insipidus has been compared with that of lysine vasopressin. DDAVP in equivalent intravenous dosage has been found to be at least as potent and to have a more prolonged action, lasting 13-22 hours instead of 1-2 hours. Twice-daily intranasal DDAVP effected satisfactory control in all these patients, without side effects, and all the patients preferred this to their previous treatment. Single daily intramuscular injections of DDAVP were found to offer excellent control for any subject unable to manage intranasal administration.     

Diabetes Insipidus in Pregnancy: Etiology,Evaluation, and Management

ObjectiveTo review the approach to a patient with diabetes insipidus during pregnancy.MethodsThis review examines the normal physiology of water homeostasis, the related changes that occur during pregnancy, and the pathophysiology of diabetes insipidus in pregnancy. Associated complications, evaluation, and management are discussed.ResultsDiabetes insipidus can complicate up to 1 in 30000 pregnancies. Diabetes insipidus during pregnancy has a variety of causes, some that predate the pregnancy and others that begin during gestation. Polyuria and polydipsia can occur or be exacerbated in women with overt or subclinical central or nephrogenic diabetes insipidus. These women have either decreased central secretory reserve or impaired renal responsiveness to vasopressin. In addition, women can experience diabetes insipidus de novo in pregnancy through the actions of placental vasopressinase, which causes accelerated degradation of vasopressin. This form of diabetes insipidus may be associated with increased complications of pregnancy, including preeclampsia. Management of central diabetes insipidus and transient diabetes insipidus of pregnancy can be achieved with 1-deamino-8-D-arginine vasopressin (desmopressin acetate) (DDAVP), a vasopressin analogue. Nephrogenic diabetes insipidus is typically resistant to both DDAVP and vasopressin and underlying causes should be addressed.ConclusionsIncreased awareness of diabetes insipidus in pregnancy may lead to early diagnosis and appropriate treatment that will reduce the risks of maternal and fetal morbidity. Overall, growing experience with DDAVP has shown that it is a safe and effective treatment for diabetes insipidus caused by a variety of factors. (Endocr Pract. 2009;15:377-382)     

Vasopressin Analogue DDAVP in Diabetes Insipidus: Clinical and Laboratory Studies

In seven patients with cranial diabetes insipidus an analogue of vasopressin, DDAVP, produced an antidiuresis lasting up to 20 hours after a single intranasal dose. Lysine vasopressin (LVP) in the same dose produced a less potent antidiuresis which lasted for only three to four hours. The plasma half life of DDAVP was 7·8 and 75·5 min for the fast and slow phases, compared with 2·5 and 14·5 min for LVP. Radioiodine-labelled DDAVP was not destroyed by incubation with late pregnancy plasma, which contains an enzyme that inactivates vasopressin. The slow metabolic clearance of DDAVP, its absorption through the nasal mucosa, and its lack of side effects make this the ideal drug for the treatment of vasopressin-sensitive diabetes insipidus. Patients usually require 10 to 20 μg DDAVP given intranasally twice daily for good clinical control of their diabetes insipidus.