- Email: [email protected]
Water Metabolism
Volume 26, Number 3
May 2006
Water Metabolism
T
he transfer of water across tight epithelia is now known at such a detailed level that billions of molecules of water traversing the membrane could be modelized and are useful teaching tools (http://www.mpibpc.gwdg.de/abteilungen/073/ gallery.html; http://www.ks.uiuc.edu/research/aquaporins). This issue of Seminars in Nephrology dwells on recent advances in basic understanding and clinical applications of water metabolism. One may remember Peter Agre sharing the 2003 Nobel Prize in chemistry with Roderick MacKinnon (http://www. hopkinsmedicine.org/press/2003/October/031008A.htm), and explaining with a single cardboard picture representing exploding oocytes (Fig 1)—ie, Xenopus oocytes transfected with complementary RNA of what later would be identified as aquaporin 1, bathed in a hypotonic solution— how he identified the first member of the large family of aquaporins. In this issue, Melvin E. Laski takes a physicist/physiologist approach to explain the astounding advances made in the past 15 years: “In 1990 the water channel was a theoretical necessity, but an unknown quantity. In the time since, the extended family of aquaporins, aquaglyceroporins, glycerol facilitator–like proteins, plant plasma membrane integral proteins, and nodulin-like proteins have been characterized and its taxonomy outlined.” The mouse is an excellent experimental model for understanding human gene function because of its anatomic, physiologic, and genetic similarities with human beings and its genome can be manipulated readily by molecular means. Alan Verkman shows that mice lacking functional aquaporin 2 (AQP2), AQP3, or AQP4 manifest various degrees of nephrogenic diabetes insipidus resulting from reduced collecting duct water permeability. His team also generated an adult, inducible mouse model of severe AQP2-nephrogenic diabetes insipidus where exon 2 of Aqp2 was removed in adult mice with Cre-LoxP. These AQP2– knock-in mice will be useful in testing possible drug therapies. Also in this issue, Jane Christensen and Soren Rittig review the pathogenesis of inherited neurohypophyseal diabetes insipidus secondary to mutations in AVP, the gene coding for AVP and neurophysin II. The mechanisms by which a mutant allele causes neurohypophyseal diabetes insipidus could involve the induction of magnocellular death as a result of the accumulation of AVP precursors within the endoplasmic re-
0270-9295/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2006.03.001
Figure 1 Dr. Peter Agre, the Nobel Prize in chemistry shared with Roderick MacKinnon, explaining the exploding oocytes.
ticulum. This hypothesis could account for the delayed onset of the disease. In addition to the cytotoxicity caused by mutant AVP precursors, the interaction between the wild-type and the mutant precursors suggest that a dominant-negative mechanism also may contribute to the pathogenesis of autosomal-dominant diabetes insipidus: errors in protein folding represent the underlying basis for many inherited diseases and also are pathogenic mechanisms for AVPR2, AQP2, and other mutants responsible for pure (loss of water only) and complex (loss of water and ions) hereditary nephrogenic disorders (see article by Daniel G. Bichet). The more frequently encountered acquired nephrogenic diabetes insipidus and the mechanistic observation of a decrease in AQP2 expression observed with different etiologies (see article by Khanna) completes the description of central and nephrogenic diabetes insipidus. The oral nonpeptide vasopressin receptor antagonists now called vaptans, vap for vasopressin, tan for antagonists, are new molecular and therapeutic tools (see article by Quittnat). The structure of these compounds imitates the structure of the native hormone AVP, and these antagonists interfere with the binding pocket of AVP. These compounds have been used to treat water-retaining disorders successfully and some of them may rescue misfolded AVPR2 mutants responsible 187
188 for X-linked nephrogenic diabetes insipidus (see article by Bichet). Last, McKinley et al present a fascinating description of thirst that includes neuroimaging studies of thirsty human subjects using positron emission tomography or functional magnetic resonance imaging. Several cortical regions become activated in human subjects with the onset of thirst. I hope
D.G. Bichet that the thirst-for-knowledge cortical regions will be activated for the readers of this issue and the enthusiasm that we share to study water metabolism will be communicated to our young fellow researchers. Daniel G. Bichet, MD Guest Editor
May 2006
Water Metabolism
T
he transfer of water across tight epithelia is now known at such a detailed level that billions of molecules of water traversing the membrane could be modelized and are useful teaching tools (http://www.mpibpc.gwdg.de/abteilungen/073/ gallery.html; http://www.ks.uiuc.edu/research/aquaporins). This issue of Seminars in Nephrology dwells on recent advances in basic understanding and clinical applications of water metabolism. One may remember Peter Agre sharing the 2003 Nobel Prize in chemistry with Roderick MacKinnon (http://www. hopkinsmedicine.org/press/2003/October/031008A.htm), and explaining with a single cardboard picture representing exploding oocytes (Fig 1)—ie, Xenopus oocytes transfected with complementary RNA of what later would be identified as aquaporin 1, bathed in a hypotonic solution— how he identified the first member of the large family of aquaporins. In this issue, Melvin E. Laski takes a physicist/physiologist approach to explain the astounding advances made in the past 15 years: “In 1990 the water channel was a theoretical necessity, but an unknown quantity. In the time since, the extended family of aquaporins, aquaglyceroporins, glycerol facilitator–like proteins, plant plasma membrane integral proteins, and nodulin-like proteins have been characterized and its taxonomy outlined.” The mouse is an excellent experimental model for understanding human gene function because of its anatomic, physiologic, and genetic similarities with human beings and its genome can be manipulated readily by molecular means. Alan Verkman shows that mice lacking functional aquaporin 2 (AQP2), AQP3, or AQP4 manifest various degrees of nephrogenic diabetes insipidus resulting from reduced collecting duct water permeability. His team also generated an adult, inducible mouse model of severe AQP2-nephrogenic diabetes insipidus where exon 2 of Aqp2 was removed in adult mice with Cre-LoxP. These AQP2– knock-in mice will be useful in testing possible drug therapies. Also in this issue, Jane Christensen and Soren Rittig review the pathogenesis of inherited neurohypophyseal diabetes insipidus secondary to mutations in AVP, the gene coding for AVP and neurophysin II. The mechanisms by which a mutant allele causes neurohypophyseal diabetes insipidus could involve the induction of magnocellular death as a result of the accumulation of AVP precursors within the endoplasmic re-
0270-9295/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2006.03.001
Figure 1 Dr. Peter Agre, the Nobel Prize in chemistry shared with Roderick MacKinnon, explaining the exploding oocytes.
ticulum. This hypothesis could account for the delayed onset of the disease. In addition to the cytotoxicity caused by mutant AVP precursors, the interaction between the wild-type and the mutant precursors suggest that a dominant-negative mechanism also may contribute to the pathogenesis of autosomal-dominant diabetes insipidus: errors in protein folding represent the underlying basis for many inherited diseases and also are pathogenic mechanisms for AVPR2, AQP2, and other mutants responsible for pure (loss of water only) and complex (loss of water and ions) hereditary nephrogenic disorders (see article by Daniel G. Bichet). The more frequently encountered acquired nephrogenic diabetes insipidus and the mechanistic observation of a decrease in AQP2 expression observed with different etiologies (see article by Khanna) completes the description of central and nephrogenic diabetes insipidus. The oral nonpeptide vasopressin receptor antagonists now called vaptans, vap for vasopressin, tan for antagonists, are new molecular and therapeutic tools (see article by Quittnat). The structure of these compounds imitates the structure of the native hormone AVP, and these antagonists interfere with the binding pocket of AVP. These compounds have been used to treat water-retaining disorders successfully and some of them may rescue misfolded AVPR2 mutants responsible 187
188 for X-linked nephrogenic diabetes insipidus (see article by Bichet). Last, McKinley et al present a fascinating description of thirst that includes neuroimaging studies of thirsty human subjects using positron emission tomography or functional magnetic resonance imaging. Several cortical regions become activated in human subjects with the onset of thirst. I hope
D.G. Bichet that the thirst-for-knowledge cortical regions will be activated for the readers of this issue and the enthusiasm that we share to study water metabolism will be communicated to our young fellow researchers. Daniel G. Bichet, MD Guest Editor