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Fluvastatin modulates renal water reabsorption in vivo through increased AQP2 availability at the apical plasma membrane of collecting duct cells

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Abstract

X-linked nephrogenic diabetes insipidus (XNDI), a severe pathological condition characterized by greatly impaired urine-concentrating ability of the kidney, is caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene. The lack of functional V2Rs prevents vasopressin-induced shuttling of aquaporin-2 (AQP2) water channels to the apical plasma membrane of kidney collecting duct principal cells, thus promoting water reabsorption from urine to the interstitium. At present, no specific pharmacological therapy exists for the treatment of XNDI. We have previously reported that the cholesterol-lowering drug lovastatin increases AQP2 membrane expression in renal cells in vitro. Here we report the novel finding that fluvastatin, another member of the statins family, greatly increases kidney water reabsorption in vivo in mice in a vasopressin-independent fashion. Consistent with this observation, fluvastatin is able to increase AQP2 membrane expression in the collecting duct of treated mice. Additional in vivo and in vitro experiments indicate that these effects of fluvastatin are most likely caused by fluvastatin-dependent changes in the prenylation status of key proteins regulating AQP2 trafficking in collecting duct cells. We identified members of the Rho and Rab families of proteins as possible candidates whose reduced prenylation might result in the accumulation of AQP2 at the plasma membrane. In conclusion, these results strongly suggest that fluvastatin, or other drugs of the statin family, may prove useful in the therapy of XNDI.

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Abbreviations

XNDI:

X-linked nephrogenic diabetes insipidus

V2R:

V2 vasopressin receptor

AQP2:

Aquaporin-2

AVP:

Arginine vasopressin

TAL:

Thick ascending limb of the loop of Henle

GGPP:

Geranylgeranyl pyrophosphate

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Acknowledgments

This work has been funded by grants from Fondazione Cassa di Risparmio di Puglia (FCRP) No. 25/2009 to G. Procino, from PRIN (Research Program of National Interest) projects to M. Svelto (20078ZZMZW), and from Fondo per gli Investimenti della Ricerca di Base-Rete Nazionale di Proteomica (RBRN07BMCT_009). We are grateful to G. Devito for the excellent technical assistance with the animal experiments. We would like to thank Prof. F. Palmisano (Department of Chemistry, University of Bari) for the helpful discussions and supervision of the HPLC measurements.

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Authors and Affiliations

  1. Department of General and Environmental Physiology, University of Bari, Bari, Italy

    Giuseppe Procino, Claudia Barbieri, Monica Carmosino, Grazia Tamma, Serena Milano, Maria Grazia Mola, Giovanna Valenti & Maria Svelto

  2. Centro di Eccellenza di Genomica in campo Biomedico ed Agrario (CEGBA), Bari, Italy

    Giovanna Valenti & Maria Svelto

  3. Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy

    Leonarda De Benedictis

  4. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), National Institutes of Health, Bethesda, MD, USA

    Yoskaly Lazo-Fernandez

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  1. Giuseppe Procino
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Correspondence to Giuseppe Procino.

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Procino, G., Barbieri, C., Carmosino, M. et al. Fluvastatin modulates renal water reabsorption in vivo through increased AQP2 availability at the apical plasma membrane of collecting duct cells. Pflugers Arch - Eur J Physiol 462, 753–766 (2011). https://doi.org/10.1007/s00424-011-1007-5

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