A systems-level analysis of bile acids effects on rat colon epithelial cells.

Bile acid diarrhea is a chronic condition caused by increased delivery of bile acids to the colon. The underlying mechanisms remain to be elucidated. To investigate genes involved in bile acid diarrhea, systems-level analyses were used on a rat bile acid diarrhea model.

Expression, regulation and function of Aquaporin-3 in colonic epithelial cells.

The human colon balances water and electrolyte absorption and secretion while also forming a barrier protecting the body from the entry of harmful components. Aquaporin-3 (AQP3) is a water, glycerol and HO transporting channel expressed in colonic epithelia. Although expression of colonic epithelial AQP3 is altered in several intestinal disorders, such as inflammatory bowel disease and irritable bowel syndrome, the regulation and specific roles of AQP3 remain to be fully defined.

Advances in aquaporin-2 trafficking mechanisms and their implications for treatment of water balance disorders.

In mammals, conservation of body water is critical for survival and is dependent on the kidneys' ability to minimize water loss in the urine during periods of water deprivation. The collecting duct water channel aquaporin-2 (AQP2) plays an essential role in this homeostatic response by facilitating water reabsorption along osmotic gradients. The ability to increase the levels of AQP2 in the apical plasma membrane following an increase in plasma osmolality is a rate-limiting step in water reabsorption, a process that is tightly regulated by the antidiuretic hormone arginine vasopressin (AVP).

Molecular characterization of an aquaporin-2 mutation causing a severe form of nephrogenic diabetes insipidus.

The water channel aquaporin 2 (AQP2) is responsible for water reabsorption by kidney collecting duct cells. A substitution of amino acid leucine 137 to proline in AQP2 (AQP2-L137P) causes Nephrogenic Diabetes Insipidus (NDI). This study aimed to determine the cell biological consequences of this mutation on AQP2 function.

The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance.

Aquaporin 2 (AQP2) mediates the osmotic water permeability of the kidney collecting duct in response to arginine vasopressin (VP) and is essential for body water homeostasis. VP effects on AQP2 occur via long-term alterations in AQP2 abundance and short-term changes in AQP2 localization. Several of the effects of VP on AQP2 are dependent on AQP2 phosphorylation and ubiquitylation; post-translational modifications (PTM) that modulate AQP2 subcellular distribution and function.

An iso-osmolar oral supplement increases natriuresis and does not increase stomal output in patients with an ileostomy: A randomised, double-blinded, active comparator, crossover intervention study.

Background: Patients with an ileostomy often experience fluid and electrolyte depletion because of gastrointestinal loss. This study aimed to compare how an iso-osmolar and a hyperosmolar oral supplement affect ileostomy output, urine production, and natriuresis as proxy measurements of water-electrolyte balance.

Methods: In a randomised, double-blinded, active comparator, crossover intervention study, we included eight adult ileostomy patients who were independent of parenteral support.

Chronic diarrhoea following surgery for colon cancer-frequency, causes and treatment options.

Purpose: The growing population of survivors after colon cancer warrants increased attention to the long-term outcome of surgical treatment. The change in bowel anatomy after resection disrupts normal gastrointestinal function and may cause symptoms. Thus, many patients surviving colon cancer have to cope with bowel dysfunction for the rest of their lives.

CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis.

The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 shRNA knockdown of CHIP in CCD cells increased AQP2 protein and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2.

Basolateral cholesterol depletion alters Aquaporin-2 post-translational modifications and disrupts apical plasma membrane targeting.

Apical plasma membrane accumulation of the water channel Aquaporin-2 (AQP2) in kidney collecting duct principal cells is critical for body water homeostasis. Posttranslational modification (PTM) of AQP2 is important for regulating AQP2 trafficking. The aim of this study was to determine the role of cholesterol in regulation of AQP2 PTM and in apical plasma membrane targeting of AQP2.

The vasopressin type 2 receptor and prostaglandin receptors EP2 and EP4 can increase aquaporin-2 plasma membrane targeting through a cAMP-independent pathway.

Apical membrane targeting of the collecting duct water channel aquaporin-2 (AQP2) is essential for body water balance. As this event is regulated by Gs coupled 7-transmembrane receptors such as the vasopressin type 2 receptor (V2R) and the prostanoid receptors EP2 and EP4, it is believed to be cAMP dependent. However, on the basis of recent reports, it was hypothesized in the current study that increased cAMP levels are not necessary for AQP2 membrane targeting.

Characterization of AQPs in Mouse, Rat, and Human Colon and Their Selective Regulation by Bile Acids.

In normal individuals, the epithelium of the colon absorbs 1.5-2 l of water a day to generate dehydrated feces. However, in the condition of bile acid malabsorption (BAM), an excess of bile acids in the colon results in diarrhea.

Regulation of the Water Channel Aquaporin-2 via 14-3-3θ and -ζ.

The 14-3-3 family of proteins are multifunctional proteins that interact with many of their cellular targets in a phosphorylation-dependent manner. Here, we determined that 14-3-3 proteins interact with phosphorylated forms of the water channel aquaporin-2 (AQP2) and modulate its function. With the exception of σ, all 14-3-3 isoforms were abundantly expressed in mouse kidney and mouse kidney collecting duct cells (mpkCCD14).

Phosphorylation and ubiquitylation are opposing processes that regulate endocytosis of the water channel aquaporin-2.

The post-translational modifications (PTMs) phosphorylation and ubiquitylation regulate plasma membrane protein function. Here, we examine the interplay between phosphorylation and ubiquitylation of the membrane protein aquaporin-2 (AQP2) and demonstrate that phosphorylation can override the previously suggested dominant endocytic signal of K63-linked polyubiquitylation. In polarized epithelial cells, although S256 is an important phosphorylation site for AQP2 membrane localization, the rate of AQP2 endocytosis was reduced by prolonging phosphorylation specifically at S269.

New insights into regulated aquaporin-2 function.

Purpose Of Review: Aquaporin-2 (AQP2) water channels in principal cells of the kidney collecting duct are essential for urine concentration. Due to application of modern technologies, progress in our understanding of AQP2 has accelerated in recent years. In this article, we highlight some of the new insights into AQP2 function that have developed recently, with particular focus on the cell biological aspects of AQP2 regulation.

Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment.

The water channel aquaporin-2 (AQP2), expressed in the kidney collecting ducts, plays a pivotal role in maintaining body water balance. The channel is regulated by the peptide hormone arginine vasopressin (AVP), which exerts its effects through the type 2 vasopressin receptor (AVPR2). Disrupted function or regulation of AQP2 or the AVPR2 results in nephrogenic diabetes insipidus (NDI), a common clinical condition of renal origin characterized by polydipsia and polyuria.

Cell biology of vasopressin-regulated aquaporin-2 trafficking.

Whole-body water balance is predominantly controlled by the kidneys, which have the ability to concentrate or dilute the urine in the face of altered fluid and solute intake. Regulated water excretion is controlled by various hormones and signaling molecules, with the antidiuretic hormone arginine vasopressin (AVP) playing an essential role, predominantly via its modulatory effects on the function of the water channel aquaporin-2 (AQP2). The clinical conditions, central and nephrogenic diabetes insipidus, emphasize the importance of the AVP-AQP2 axis.

Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING.

The innate immune system senses infection by detecting either evolutionarily conserved molecules essential for the survival of microbes or the abnormal location of molecules. Here we demonstrate the existence of a previously unknown innate detection mechanism induced by fusion between viral envelopes and target cells. Virus-cell fusion specifically stimulated a type I interferon response with expression of interferon-stimulated genes, in vivo recruitment of leukocytes and potentiation of signaling via Toll-like receptor 7 (TLR7) and TLR9.

Vasopressin-independent targeting of aquaporin-2 by selective E-prostanoid receptor agonists alleviates nephrogenic diabetes insipidus.

In the kidney, the actions of vasopressin on its type-2 receptor (V2R) induce increased water reabsorption alongside polyphosphorylation and membrane targeting of the water channel aquaporin-2 (AQP2). Loss-of-function mutations in the V2R cause X-linked nephrogenic diabetes insipidus. Treatment of this condition would require bypassing the V2R to increase AQP2 membrane targeting, but currently no specific pharmacological therapy is available.

Regulation of the water channel aquaporin-2 by posttranslational modification.

The cellular functions of many eukaryotic membrane proteins, including the vasopressin-regulated water channel aquaporin-2 (AQP2), are regulated by posttranslational modifications. In this article, we discuss the experimental discoveries that have advanced our understanding of how posttranslational modifications affect AQP2 function, especially as they relate to the role of AQP2 in the kidney. We review the most recent data demonstrating that glycosylation and, in particular, phosphorylation and ubiquitination are mechanisms that regulate AQP2 activity, subcellular sorting and distribution, degradation, and protein interactions.

Differential water permeability and regulation of three aquaporin 4 isoforms.

Aquaporin 4 (AQP4) is expressed in the perivascular glial endfeet and is an important pathway for water during formation and resolution of brain edema. In this study, we examined the functional properties and relative unit water permeability of three functional isoforms of AQP4 expressed in the brain (M1, M23, Mz). The M23 isoform gave rise to square arrays when expressed in Xenopus laevis oocytes.

Phosphorylation of aquaporin-2 regulates its endocytosis and protein-protein interactions.

The water channel aquaporin-2 (AQP2) is essential for urine concentration. Vasopressin regulates phosphorylation of AQP2 at four conserved serine residues at the COOH-terminal tail (S256, S261, S264, and S269). We used numerous stably transfected Madin-Darby canine kidney cell models, replacing serine residues with either alanine (A), which prevents phosphorylation, or aspartic acid (D), which mimics the charged state of phosphorylated AQP2, to address whether phosphorylation is involved in regulation of (i) apical plasma membrane abundance of AQP2, (ii) internalization of AQP2, (iii) AQP2 protein-protein interactions, and (iv) degradation of AQP2.

Identification of phosphorylation-dependent binding partners of aquaporin-2 using protein mass spectrometry.

Vasopressin-mediated control of water permeability in the renal collecting duct occurs in part through regulation of the distribution of aquaporin-2 (AQP2) between the apical plasma membrane and intracellular membrane compartments. Phosphorylation of Ser-256 at AQP2's cytoplasmic COOH-terminus is well-accepted as a critical step for translocation. The aim of this study was to identify binding partners to phosphorylated versus nonphosphorylated forms of the AQP2 COOH-terminus via a targeted comparative proteomic approach.