Nephrogenic Diabetes Insipidus: Essential Insights into the Molecular Background and Potential Therapies for Treatment

Abstract

The water channel aquaporin-2 (AQP2), expressed in the kidney collecting ducts, plays a pivotal role in maintaining body water balance. The channel is regulated by the peptide hormone arginine vasopressin (AVP), which exerts its effects through the type 2 vasopressin receptor (AVPR2). Disrupted function or regulation of AQP2 or the AVPR2 results in nephrogenic diabetes insipidus (NDI), a common clinical condition of renal origin characterized by polydipsia and polyuria. Over several years, major research efforts have advanced our understanding of NDI at the genetic, cellular, molecular, and biological levels. NDI is commonly characterized as hereditary (congenital) NDI, arising from genetic mutations in the AVPR2 or AQP2; or acquired NDI, due to for exmple medical treatment or electrolyte disturbances. In this article, we provide a comprehensive overview of the genetic, cell biological, and pathophysiological causes of NDI, with emphasis on the congenital forms and the acquired forms arising from lithium and other drug therapies, acute and chronic renal failure, and disturbed levels of calcium and potassium. Additionally, we provide an overview of the exciting new treatment strategies that have been recently proposed for alleviating the symptoms of some forms of the disease and for bypassing G protein-coupled receptor signaling.

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

“…The most common adverse effect of Li + therapy, affecting approximately 50% of patients, is Li + -induced nephrogenic diabetes insipidus (Li-NDI), characterized by polydipsia, polyuria, and a limited renal response to the antidiuretic hormone, arginine vasopressin (AVP) (2). The polyuric effects of Li + are associated with a marked decrease in the abundance of the water channel aquaporin-2 (AQP2) in collecting duct (CD) principal cells (PCs), accompanied by a large increase in the ratio of intercalated cells (ICs) to PCs along the CD system (3,4).…”

Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis

“…Binding of AVP to the V2R leads to cAMP-mediated translocation of aquaporin-2 to the apical plasma membrane. This regulation of aquaporin-2 water channel localization is crucial for increasing urine osmolality and reducing urine output in humans (3). For precise regulation, the signal transduction of the activated GPCR has to be terminated to limit the effect in the target cells (4).…”

Identification of an AVP-NPII mutation within the AVP moiety in a family with neurohypophyseal diabetes insipidus: review of the literature

“…This pattern of the majority of mutations in FNDI located in the NPII moiety followed by the signalling peptide of the AVP precursor has been consistent in a large number of unrelated FNDI kindred studies since then. 20 Nevertheless, studies have found a few cases of autosomal dominant mutations associated with FNDI affecting specifically positions 2 and 3 of AVP ( Figure 1B). Rittig et al 8 found the same missense mutation identified in the present study in Turkish kindred with FNDI.…”