Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update

Abstract

Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.

Keywords: antidiuresis; aquaporin-2 (AQP2); arginine-vasopressin (AVP); arginine-vasopressin receptor AVPR2; nephrogenic diabetes insipidus (NDI); polyuria.

Figure 1

Action of arginine vasopressin (AVP) in the collecting duct principal cells. Upon the binding of AVP to its cognate receptor AVPR2 at the basolateral membrane, a stimulatory G protein α subunit (G_s) activates adenylyl cyclase and increases cyclic adenosine monophosphate (cAMP) intracellular concentrations. This, in turn, activates protein kinase A (PKA), which phosphorylates many substrates, including AQP2 and RhoA (full lines). The partial depolymerization of the sub-apical actin cytoskeleton facilitates the apical exocytosis of AQP2-storage vesicles (dotted lines). Water enters the cells via de novo inserted AQP2 tetramers at the apical membrane and leaves the epithelial cells through AQP3 and AQP4 constitutively expressed at the basolateral membrane. AVP removal from the bloodstream allows AQP2 endocytosis and recycling through early endosomes (dotted lines).

Figure 2

The current possible strategies to bypass AVPR2 mutations responsible for X-linked NDI. The most recurrent mutations of AVPR2 responsible for X-linked NDI are class II mutations producing full-length misfolded proteins trapped in the endoplasmic reticulum (ER), although retaining intrinsic functionality. A lack of AVPR2 basolateral expression prevents AVP signaling and AQP2 exocytosis (grey dotted lines). Possible therapeutic strategies (full lines) for treating X-linked NDI are focused on: (1) the use of chemical chaperones aiding protein folding and inducing export from the ER; nonpeptide AVPR2 antagonists, like vaptans, that stabilize receptor conformation in the ER, thus allowing it to bypass the ER quality control mechanism; and nonpeptide AVPR2 agonists that promote interaction with adenylyl cyclase, thus increasing cAMP concentration (+). (2) Activation of the cAMP pathway by stimulating other G proteins-coupled receptors (GPCRs) coupled to Gs/adenylyl cyclase expressed in collecting duct principal cells such as secretin (SCT), calcitonin (CT), E-prostanoid receptors (EP2/EP3/EP4) and β3-adrenoreceptor; the inhibition of phosphodiestherases (PDE) to increase basal cAMP levels (+). (3) The activation of the cyclic guanosine monophosphate (cGMP) pathway, promoting AQP2 exocytosis either by stimulating guanylyl cyclase or by inhibiting PDE. (4) The inhibition of epidermal growth factor receptor (EGFR), which counteracts AVP-mediated AQP2 exocytosis by a not fully elucidated mechanism. (5) The activation of AMP-activated protein kinase (AMPK) promoting AVP-independent AQP2 phosphorylation. (6) Thiazolidinediones (Rosiglitazone) likely promotes Ca²⁺ influx that triggers AQP2 exocytosis at the plasma membrane in the absence of AQP2 phosphorylation. (7) Statins treatment that inhibits RhoA, promotes cortical actin depolymerization, and facilitates the constitutive exocytosis of AQP2 at the apical membrane.

Figure 3

AQP2 mutations explain autosomal recessive and dominant NDI. AQP2 mutations can affect the proper synthesis, processing or plasma membrane localization of the gene product. Most of the AQP2 mutations falling in the protein transmembrane domains are misfolded (yellow tetramers) and retained in the ER until degraded by the proteasome. Affected patients are homozygous or compound heterozygous for these AQP2 mutations. Since most of these mutants still maintain water channel functionality, the therapeutic approach under investigation is based on the use of chemical chaperones aiding release from the ER (full lines). Autosomal dominant NDI is caused by AQP2 mutations affecting the carboxyl terminus (COOH-terminus) of the protein, which is a crucial domain for phosphorylation or apical sorting. A lack of AQP2 exocytosis (dotted lines) prevent the AVP-mediated water reabsorption in the collecting duct principal cells.These AQP2 mutants have a dominant effect over the wtAQP2 subunit and are responsible for AQP2 missorting.