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

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.

New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

“…In combination with results from others showing a similar effect of lovastatin on urine concentration in normal mice (102), these data provide compelling evidence that a blockade of AQP2 endocytosis can be harnessed to increase urineconcentrating ability, perhaps ultimately in humans. There are of course several caveats before such therapy can be translated to the human condition.…”

Rab GTPases regulate the trafficking of channels and transporters – a focus on cystic fibrosis

“…Fluvastatin reduced the isoprenylation of RhoA and Rab5 GTPases, resulting in decreased membrane tethering these proteins and the accumulation of AQP2 at the PM. 53 Because Rab5a was found upregulated in CF bronchial cell lines, 18 it might be useful to ascertain whether statins administration would benefit CF patients bearing mutations that decrease CFTR stability at the apical surface of airway cells.…”

Fluvastatin Increases AQP2 Urine Excretion in a Dyslipidemic Patient with Nephrogenic Diabetes Insipidus: An In Vivo and In Vitro Study

“…Among the plethora of candidate molecules that could improve the effect of the current therapy for XNDI, we demonstrated that statins induce an AVP-independent accumulation of AQP2 at the plasma membrane of collecting duct cells in vitro and in vivo in both wild type and XNDI mice, greatly improving kidney concentrating ability [23,[25][26][27].…”

“…Cardiovascular risk factors were estimated and the patient was considered eligible for statin therapy. Fluvastatin was chosen because of our previous report showing an effect of this drug on AQP2 plasma membrane expression in the hope that this statin could also ameliorate NDI symptoms [23,27]. Informed consent was obtained prior to entering the subject into this study.…”