Seminar

Seminar

Date:
12 May 2011 00:00 hrs.
Location:
Title:
Aquaporin 2: more than a water channel?
Speaker(s):

Prof. Dennis Brown, Professor of Medicine, Harvard Medical School, Director, MGH Program in Membrane Biology, Division of Nephrology

Host(s):

Prof. Peter Deen, Department of Physiology, RUNMC, Nijmegen

12-05-2011 00:00:00Europe/AmsterdamAquaporin 2: more than a water channel? Rimlsrimls@radboudumc.nl

Remarks / more information:

Dennis-BrownThe aquaporin 2 (AQP2) water channel is expressed in kidney collecting ducts (CD) and responds to the antidiuretic hormone vasopressin by accumulating on the plasma membrane of principal cells. This increases their water permeability, and allows urinary concentration to occur by osmotic equilibration with the renal interstitium. By understanding different intracellular signal transduction pathways and mechanisms that are involved in this process, it has been possible to bypass the vasopressin receptor signaling pathway to induce cell surface accumulation of AQP2 in cell models and whole animals. The first part of this presentation will discuss work from our Program that has resulted in three strategies to bypass defective V2R signaling, which is a cause of X-linked nephrogenic diabetes insipidus (NDI). The first is the use of an alternative G-protein coupled receptor pathway activated by calcitonin. This pathway is cAMP linked, and its stimulation results in AQP2 membrane accumulation and increased urinary concentration in rats. The second involves a cGMP-linked pathway, activated using the PDE5 inhibitor, sildenafil (Viagra). In rats, this drug causes increased membrane expression of AQP2, but no short-term increase in urinary concentration, probably due to its parallel effect on renal blood flow and GFR. The third pathway involves the use of statins (simvastatin) to depolymerize the actin cytoskeleton via an inhibitory effect on RhoA prenylation. In just 1 h, statins cause a dose-dependent increase in membrane AQP2 accumulation by their effect on actin, and significantly increase urinary concentration in VP-deficient Brattleboro rats. The second part of the talk will discuss our recent unexpected discovery that AQP2 is an integrin binding protein that is involved in cell migration and epithelial morphogenesis. These effects are mediated by an extracellular RGD domain on AQP2, and are independent of its water channel properties. A team within our Program, led by Hua Jenny Lu, has shown that AQP2 mediates its effect by modulating the trafficking of integrins to the basolateral cell surface, and inhibiting cell migration by reducing the turnover and mobility of focal adhesions. Furthermore, mutation of the RGD site on AQP2 leads to epithelial cyst formation in 3-dimensional cell cultures in vitro. These data are consistent with prior work on AQP2 null mice or mice with knockin of an AQP2 trafficking mutation that all show renal morphological abnormalities and dilated or cystic CDs, with increased postnatal mortality. Thus, AQP2 is more than an apical water channel. It interacts with integrins in the basolateral trafficking pathway to modulate epithelial cell morphogenesis and may be required for development of the collecting duct system in the mammalian kidney.



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