Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing.

Deen, Peter M.T.; Croes, H.J.E.; Aubel, R.A.M.H. van; Ginsel, L.A.; Os, C.H. van

doi:10.1172/jci117920

Cited by 229 publications

(153 citation statements)

References 33 publications

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“…The MRP3 staining pattern paralleled the staining observed with a polyclonal antiserum against the Tamm-Horsfall protein, known to be localized in the early distal convoluted tubules and the thick ascending loops of Henle (Sikri et al, 1981) (Fig. 3d), but not with the staining for aquaporin-2, identifying the collecting ducts (Deen et al, 1995;Nielsen et al, 1993) (Fig. 3f).…”

Section: Kidneysupporting

confidence: 59%

Tissue Distribution and Induction of Human Multidrug Resistant Protein 3

Scheffer

Kool

Haas

et al. 2002

Laboratory Investigation

242

156

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SUMMARY:The multidrug resistance protein (MRP) family consists of several members and, for some of these transporter proteins, distinct roles in multidrug resistance and normal tissue functions have been well established (MRP1 and MRP2) or are still under investigation (MRP3). MRP3 expression studies in human tissues have been largely restricted to the mRNA level. In this report we extended these studies and further explored MRP3 expression at the protein level. Western blot and immunohistochemistry with two MRP3-specific monoclonal antibodies, M 3 II-9 and M 3 II-21, showed MRP3 protein to be present in adrenal gland, and kidney and in tissues of the intestinal tract: colon, pancreas, gallbladder, and liver. In epithelia, MRP3 was found to be located at the basolateral sides of cell membranes. In normal liver, MRP3 was detected at lower levels than anticipated from the mRNA data and was found present mainly in the bile ducts. In livers from patients with various forms of cholestasis, MRP3 levels were frequently increased in the proliferative cholangiocytes, with sometimes additional staining of the basolateral membranes of the hepatocytes. This was especially evident in patients with type 3 progressive familial intrahepatic cholestasis. The present results support the view that MRP3 plays a role in the cholehepatic and enterohepatic circulation of bile and in protection within the biliary tree and tissues along the bile circulation route against toxic bile constituents. The possible functional roles for MRP3 in the adrenal gland and in the kidney remain as yet unknown. In a panel of 34 tumor samples of various histogenetic origins, distinct amounts of MRP3 were detected in a limited number of cases, including lung, ovarian, and pancreatic cancers. These findings may be of potential clinical relevance when considering the drug treatment regimens for these tumor types. (Lab Invest 2002, 82:193-201).

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Section: Kidneysupporting

confidence: 59%

Tissue Distribution and Induction of Human Multidrug Resistant Protein 3

Scheffer

Kool

Haas

et al. 2002

Laboratory Investigation

242

156

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“…15,16 In states of hypernatremia or hypovolemia, translocation of phosphorylated AQP2 homotetramers from vesicles to the apical plasma membrane of the principal cells is triggered by a signal transduction cascade induced by arginine-vasopressin. 16 -18 Alike to normal human kidney, 19 wild-type (wt) AQP2, when expressed in Xenopus oocytes 20,21 or various mammalian cell lines, 18,22 existed as a nonglycosylated 29-kd form. Autosomal recessive NDI-causing mutants expressed in Xenopus oocytes were detected as a nonglycosylated 29-kd and an endo H-sensitive, high-mannose 32-kd form.…”

Section: Mutations In the Water Channel Aquaporin-2 (Aqp2) Can Cause mentioning

confidence: 99%

“…Autosomal recessive NDI-causing mutants expressed in Xenopus oocytes were detected as a nonglycosylated 29-kd and an endo H-sensitive, high-mannose 32-kd form. 20 But only a 29-kd form was observed in transiently transfected Chinese hamster ovary (CHO) 22 or LLC-PK1 cells. 23 The autosomal dominant NDI-causing E258K AQP2 existed as a 29-kd form both in Xenopus oocytes 24 and in transiently transfected CHO cells.…”

Section: Mutations In the Water Channel Aquaporin-2 (Aqp2) Can Cause mentioning

confidence: 99%

“…22 Heterologous expression has provided evidence for an impaired routing of mutant AQP2 proteins. In many of the autosomal recessive NDI-causing AQP2 mutations, retention of the mutant protein in the ER was reported 20,23,25 whereas the autosomal dominant NDI-causing E258K AQP2 was localized in the Golgi apparatus. 24 Expression of the ER-retained T126M AQP2 in clone 9 hepatocytes caused the formation of Mallory body-type inclusion bodies probably because of ER stress.…”

Section: Mutations In the Water Channel Aquaporin-2 (Aqp2) Can Cause mentioning

confidence: 99%

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The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Hirano

Zuber

Roth

et al. 2003

The American Journal of Pathology

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Mutations in the water channel aquaporin-2 (AQP2) can cause congenital nephrogenic diabetes insipidus. To reveal the possible involvement of the protein quality control system in processing AQP2 mutants, we created an in vitro system of clone 9 hepatocytes stably expressing endoplasmic reticulum-retained T126M AQP2 and misrouted E258K AQP2 as well as wild-type AQP2 and studied their biosynthesis, degradation, and intracellular distribution. Mutant and wild-type AQP2 were synthesized as 29-kd nonglycosylated and 32-kd core-glycosylated forms in the endoplasmic reticulum. The wild-type AQP2 had a t 1/2 of 4.6 hours. Remarkable differences in the degradation kinetics were observed for the glycosylated and nonglycosylated T126M AQP2 (t 1/2 ‫؍‬ 2.0 hours versus 0.9 hours). Moreover, their degradation was depending on proteasomal activity as demonstrated in inhibition studies. Degradation of E258K AQP2 also occurred rapidly (t 1/2 ‫؍‬ 1.8 hours) but in a proteasome-and lysosome-dependent manner. By triple confocal immunofluorescence microscopy misrouting of E258K to lysosomes via the Golgi apparatus could be demonstrated. Notwithstanding the differences in degradation kinetics and subcellular distribution such as endoplasmic reticulum-retention and misrouting to lysosomes, both T126M and E258K AQP2 were efficiently degraded. This implies the involvement of different protein quality control processes in the processing of these AQP2 mutants. The endoplasmic reticulum (ER) represents a site of quality control of glycoprotein folding. 1,2 Misfolded glycoproteins are recognized and retained by the concerted action of chaperones, lectins, and modifying enzymes such as UDP-glucose:glycoprotein glucosyltransferase and glucosidase II. 3 Glycoproteins failing to achieve their correct conformation might become retrotranslocated to the cytosol 4 and degraded by the ubiquitin-proteasome pathway, a process referred to as ER-associated protein degradation. [5][6][7] Quality control of protein folding is of importance in congenital diseases caused by point mutations that result in the synthesis of misfolded glycoproteins. 8 Mutations in the water channel aquaporin-2 (AQP2) can cause nephrogenic diabetes insipidus (NDI), in which patients are unable to concentrate urine in response to the anti-diuretic hormone arginine-vasopressin. 9 -11 If not corrected, this defect results in a deregulated whole-body water homeostasis that is accompanied by various symptoms of dehydration. 12 AQP2 belongs to the large family of AQPs, 13,14 and is a 29-kd polytope membrane protein that contains a single N-glycosylation site and two phosphorylation sites, and is present in the principal cells of renal collecting ducts. 15,16 In states of hypernatremia or hypovolemia, translocation of phosphorylated AQP2 homotetramers from vesicles to the apical plasma membrane of the principal cells is triggered by a signal transduction cascade induced by arginine-vasopressin. 16 -18 Alike to normal human kidney, 19 wild-type (wt) AQP2, when expressed in Xenopus ooc...

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“…An emerging paradigm is the therapy of protein folding diseases by chemical or molecular chaperones, which may facilitate folding of the mutant protein by direct binding and/or modulation of components of the molecular quality control machinery. T126M is one of several AQP2 mutations that cause autosomal recessive NDI (24). Analysis of AQP2-T126M folding at the endoplasmic reticulum in mammalian cell culture models indicated ER retention, with remarkable resistance to membrane extraction by non-ionic detergents (25).…”

Section: Mouse Models Of Aqp2 Gene Mutation/deletionmentioning

confidence: 99%

Dissecting the Roles of Aquaporins in Renal Pathophysiology Using Transgenic Mice

Verkman

2008

Seminars in Nephrology

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Transgenic mice lacking renal aquaporins (AQPs), or containing mutated AQPs, have been useful in confirming anticipated AQP functions in renal physiology and in discovering new functions. Mice lacking AQPs 1-4 manifest defects in urinary concentrating ability to different extents. Mechanistic studies have confirmed the involvement of AQP1 in near-isosmolar fluid absorption in proximal tubule, and in countercurrent multiplication and exchange mechanisms that produce medullary hypertonicity in the antidiuretic kidney. Deletion of AQPs 2-4 impairs urinary concentrating ability by reduction of transcellular water permeability in collecting duct. Recently created transgenic mouse models of nephrogenic diabetes insipidus produced by AQP2 gene mutation offer exciting possibilities to test new drug therapies. Several unanticipated AQP functions in kidney have been discovered recently that are unrelated to their role in transcellular water transport. There is evidence for involvement of AQP1 in kidney cell migration following renal injury, of AQP7 in renal glycerol clearance, of AQP11 in prevention of renal cystic disease, and possibly of AQP3 in regulation of collecting duct cell proliferation. Future work in renal AQPs will focus on mechanisms responsible for these non-fluid-transporting functions, and on the development of small-molecule AQP inhibitors for use as aquaretic-type diuretics.

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Water channels encoded by mutant aquaporin-2 genes in nephrogenic diabetes insipidus are impaired in their cellular routing.

Cited by 229 publications

References 33 publications

Tissue Distribution and Induction of Human Multidrug Resistant Protein 3

Tissue Distribution and Induction of Human Multidrug Resistant Protein 3

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Dissecting the Roles of Aquaporins in Renal Pathophysiology Using Transgenic Mice

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