Potential of Nonpeptide (Ant)agonists to Rescue Vasopressin V2 Receptor Mutants for the Treatment of X‐linked Nephrogenic Diabetes Insipidus

Abstract

Maintaining the water homeostasis of the body is crucial for its proper functioning. Accordingly, water and electrolytes are balanced by a carefully orchestrated interplay between volume-and osmoregulation that is regulated by multiple hormones. A key hormone in process is the antidiuretic hormone arginine-vasopressin (AVP), which is released from the pituitary in states of hypernatreamia or hypovolaemia (1, 2).The main target organ of AVP in the process of osmoregulation is the kidney, which is composed of approximately one million nephrons, the functional units in kidney. In these nephrons, ultrafiltration results in the formation of a daily volume of approximately 180 l of pro-urine. Of this large volume, approximately 99% of the water is reabsorbed by the tubular epithelial cells of the nephron, whereas only 1.5-2 l of water is excreted via the urine. Approximately 90% of the tubular water reabsorption occurs in the proximal tubules and descending loop of Henle, where water is reabsorbed iso-osmotically via the water channel aquaporin-1. The remaining 9% can be reabsorbed in the principal cells of the collecting duct, the final part of the nephron, and is regulated by AVP. Binding of AVP to its type 2 receptor on the basolateral (interstitial) side of the principal cells induces a cAMP cascade that increases protein levels of the water channel aquaporin-2 (AQP2) and triggers the protein kinase A-induced translocation of AQP2 storage vesicles to the apical (luminal) plasma membrane (Fig. 1A) (1). Insertion of AQP2 in this membrane facilitates its water permeability and allows water transport from the tubular lumen into the principal cells, and its subsequent flow into the interstitium via the water channels aquaporin-3 and 4 in the basolateral plasma membrane. Together, this allows the body to retain water and compensate for states of hypernatraemia or hypovolaemia. When the water balance is restored, AVP release will lead to decreased plasma AVP levels and thereby to the retrieval of AQP2 from the apical membrane, rendering the collecting duct impermeable to water (1).Disturbances in the above process will result in diabetes insipidus (DI), a disease characterised by polyuria and compensatory polydipsia. The underlying causes of DI are diverse and can be a central defect, in which no functional AVP is released from the pituitary, or may be caused by defects in the kidney (nephrogenic DI, NDI). Four Journal of NeuroendocrinologyCorrespondence to: Joris H. Robben, 286 Deptartment of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (e-mail: j.robben@fysiol.umcn.nl).According to the body's need, water is reabsorbed from the pro-urine that is formed by ultrafiltration in the kidney. This process is regulated by the antidiuretic hormone arginine-vasopressin (AVP), which binds to its type 2 receptor (V2R) in the kidney. Mutations in the gene encoding the V2R often lead to the X-linked inheritable form of nephrogenic diabetes insipidus (ND...

Diabetes Insipidus: A Review

“…Other potential treatments for NDI include possible rescue of trapped V 2 receptors stuck in the endoplasmic reticulum, as seen with class II mutations [78,135]. Rescue of these receptors via chemical compounds known as nonpeptide chaperones looks to be promising [78]. These nonpeptide chaperones stabilize the V 2 receptor trapped in the endoplasmic reticulum of the collecting duct cells.…”

“…DDAVP usually has no effect on patients with NDI but may be effective in patients with partial resistance to ADH; therefore, it is worthwhile to try a high dose of DDAVP [134]. Other potential treatments for NDI include possible rescue of trapped V 2 receptors stuck in the endoplasmic reticulum, as seen with class II mutations [78,135]. Rescue of these receptors via chemical compounds known as nonpeptide chaperones looks to be promising [78].…”

“…There are 5 classes of V 2 receptor mutations leading to NDI [1,77]: (I) Abnormal mRNA that is untranslated or leads to aborted proteins (II) Translated proteins that are trapped in the endoplasmic reticulum (III) Proteins that are in the correct location but do not signal in response to ADH (IV) Proteins that are in the correct location but do not bind ADH (V) Proteins that are transported to improper organelles [77]. Close to half of X-linked NDI is due to class II mutations [77,78]. These class II mutations are resultant of a missense mutation.…”

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“…This can be done with the help of chemicals known as nonpeptide chaperones. 74,75 Recent studies have shown that gene therapy can be the better option for treatment of NDI but it is highly speculative. 24 Recent investigations have revealed that statins also increase the expression of AQP2 in apical membrane.…”