Abstract

The water channel Aquaporin 2 (AQP2) is responsible for the vasopressin (VP)-dependent water reabsorption occurring in the kidney during antidiuresis. X-linked nephrogenic diabetes insipidus (XNDI), a severe rare disease characterized by impaired urine-concentrating ability of the kidney, is caused by inactivating mutations in the V2 type VP receptor (V2R) gene. Mutation prevents the VP-induced shuttling of AQP2 from intracellular storage vesicles to the apical plasma membrane of kidney collecting duct principal cells. This, in turn, dramatically reduces water reabsorption resulting in severe polyuria and constant risk of dehydration. Unfortunately, the current pharmacological approach for handling XNDI is unable to rescue AQP2 membrane expression. We have previously reported that the cholesterol-lowering drug lovastatin increases AQP2 membrane expression in renal cells in vitro. More recently we reported that, in mice, fluvastatin increases AQP2 membrane expression in the collecting duct in a VP-independent fashion and greatly increases the amount of water reabsorbed in the kidney. Additional experiments in vitro, performed on a cell culture model recapitulating AQP2 trafficking, indicate that this effect of fluvastatin is most likely caused by the statin-dependent inhibition of protein prenylation of key regulators of AQP2 trafficking in collecting duct cells. We identified members of the Rho and Rab families of proteins as possible key players whose reduced prenylation might result in the accumulation of AQP2 at the plasma membrane, by modulating the basal rate of exocytosis and/or endocytosis. Most importantly, preliminary results obtained using the conditional mouse model of human XNDI, characterized by severe polyuria and low urine osmolality, indicate that fluvastatin treatment significantly reduces diuresis and increases urine osmolality. Taken together, these results strongly suggest that statins may prove useful in the therapy of XNDI.

Autore Pugliese

• Valenti Giovanna , Procino Giuseppe

Tutti gli autori

• VALENTI G.;PROCINO G.;SVELTO M.

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Anno di pubblicazione

2012

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