AQUAPORIN 2 AND CALCIUM SENSING RECEPTOR: NEW PLAYERS REGULATING RENAL WATER HANDLING IN FAMILIAL HYPERCALCIURIA

Humans consist for more 70% of water. Since their adaptation to a terrestrial living, the limited supply of water urged these organisms to tightly control their water homeostasis. The kidney plays a critical role in regulating water homeostasis through specific proteins highly expressed in the kidney, called aquaporins, allowing water permeation at high rate. Since this latter process is implicated in many forms of acquired and genetic disorders, identification of the key proteins and mechanisms underlying the normal and disturbed processes has been a major topic of research during the last 10 years.This project is aimed at studying some inherited nephropathies associated with impaired urinary concentrating ability and specifically analyze the role of aquaporin 2 dysregulation in those disorders. Impaired water handling in genetic nephropathies could be monitored by measuring urinary aquaporin 2. Indeed, as the proponent recently demonstrated, urinary aquaporin 2 has been proven to be a valuable marker in the clinical condition with altered water balance, the nocturnal enuresis, a common, genetic and heterogeneous disorder (Valenti et al. 2000). Specifically, we propose to study the relationship between hypercalciuria (high calcium levels in the urine) and impaired aquaporin 2 -mediated water handling in inherited disorders characterized by hypercalciuria, such as those affecting the ‘sensor of extracellular calcium concentration, the calcium sensing receptor, which represents the principal target for extracellular calcium regulation of several tissues including parathyroid glands and kidney. Understanding the molecular genetic of alteration of kidney concentrating ability found in hypercalciuria will help for devising strategies for reducing the risk of nephrocalcinosis, nephrolithiasis, and renal insufficiency.