Methyl-β-cyclodextrin induces vasopressin-independent apical accumulation of aquaporin-2 in the isolated, perfused rat kidney

American Journal of Physiology - Renal Physiology - Tập 291 Số 1 - Trang F246-F253 - 2006
Leileata M. Russo1, Mary McKee, Dennis Brown
1Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital/Harvard Medical School, Simches Research Center, 185 Cambridge St, Rm 8100, Boston, MA 02114, USA. [email protected]

Tóm tắt

Vasopressin increases urine concentration by stimulating plasma membrane accumulation of aquaporin-2 (AQP2) in collecting duct principal cells, allowing bulk water flow across the collecting duct from lumen to interstitium down an osmotic gradient. Mutations in the vasopressin type 2 receptor (V2R) cause hereditary X-linked nephrogenic diabetes insipidus (NDI), a disease characterized by excessive urination and dehydration. Recently, we showed that inhibition of endocytosis by the cholesterol-depleting drug methyl-β-cyclodextrin (mβCD) induces plasma membrane accumulation of AQP2 in transfected renal epithelial cells overexpressing epitope-tagged AQP2. Here, we asked whether mβCD could induce membrane accumulation of AQP2 in situ using the isolated, perfused kidney (IPK). By immunofluorescence and electron microscopy, we show that AQP2 was shifted from a predominantly intracellular localization to the apical membrane of principal cells following 1-h perfusion of Sprague-Dawley rat kidneys with 5 mM mβCD. Quantification of staining revealed that the intensity of AQP2 was increased from 647 ± 114 (control) to 1,968 ± 299 units (mβCD; P < 0.001), an effect similar to that seen after perfusion with 4 nM dDAVP (1,860 ± 298, P < 0.001). Similar changes were observed following mβCD perfusion of kidneys from vasopressin-deficient Brattleboro rats. No effect of mβCD treatment on the basolateral distribution of AQP3 and AQP4 was detected. These data indicate that AQP2 constitutively recycles between the apical membrane and intracellular vesicles in principal cells in situ and that inducing apical AQP2 accumulation by inhibiting AQP2 endocytosis is a feasible goal for bypassing the defective V2R signaling pathway in X-linked NDI.

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American Journal of Physiology - Renal Physiology

Tập 291 Số 1

F246-F253

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