Molecular Mechanisms Controlling Transmembrane Transport

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The binding of VEGF dimers to tyrosine-kinase receptors VEGFR-1 and VEGFR-2 located in endothelial cells initiates a signal transduction cascade responsible for endothelial proliferation and migration, activation of plasminogen and collagenase, and vasodilation, all these steps resulting in physiological angiogenesis Stimuli for VEGF expression include hypoxia, hypoglycemia, cytokines such as interleukin-6 IL-6 , growth factors, and hormones 28, VEGF is synthesized by cultured mesothelial and endothelial cells isolated from the peritoneum 24, and its expression is upregulated in long-term PD patients By analogy with other angiogenic diseases, it is tempting to speculate that the upregulation of VEGF may trigger vascular proliferation in the PM in long-term PD.

Of note, plasma and dialysate concentrations of VEGF and IL-6 have recently been associated with high peritoneal solute transport rate Nitric oxide is an attractive candidate to regulate EPSA and UF during PD, given its crucial role in the regulation of vascular tone and permeability 31 and its interactions with angiogenic growth factors The paradigm has been provided by the loss of UF in a rat model of acute peritonitis, characterized by the upregulation of the endothelial and inducible NOS isoforms and a parallel increase in the permeabillity for glucose and small solutes Other effect of NO that may affect the PM include generation of the powerful oxidant peroxynitrite 15, and post-translational modifications such as S-nitrosylation That hypothesis has recently been supported by the association of several molecular mechanisms --upregulation of NOS, high levels of circulating RCOs and AGEs, increased growth factors-- with higher peritoneal permeability in a chronic uremic rat model Diabetes may represent another factor that affect the PM.

The CANUSA prospective study showed a greater proportion of diabetics among high transporter PD patients 3, and it has been suggested that diabetic patients have higher permeability for creatinine and lower UF than non-diabetic patients 35, Recent studies performed in a streptozotocin-induced diabetic rat model 17, 18 showed that chronic hyperglycemia alone is sufficient to induce functional increased permeability for small solutes and structural areas of vascular proliferation changes in the PM, in parallel with the selective regulation of NOS isoforms and AGEs deposits All the alterations were prevented by chronic insulin treatment, demonstrating that adequate control of glycemia in this diabetic rat model is sufficient to preserve PM integrity Taken together, these data suggest an independent contribution of uremia and hyperglycemia in peritoneal changes during PD.

The twochamber system separates highly concentrated glucose from other components, allowing to sterilize glucose at a very low pH. Mixing of the two compartments results in a solution characterized by a very low level of GDPs and a more physiologic pH, and in which bicarbonate can replace lactate as buffer When tested in vitro, such biocompatible dialysates have been shown to reduce AGE formation 38; decrease acute vasoactive effects on the peritoneal circulation 39; and improve ex vivo peritoneal macrophage function Two randomized clinical trials using such solutions have shown no significant modifications of peritoneal transport parameters but an increase in dialysate CA taken as a marker of mesothelial cell mass and a decrease in dialysate hyaluronan taken as a marker of peritoneal inflammation 41, Glucose-free PD solutions including icodextrin and amino-acids have also been recently introduced in order to minimize the deleterious effect of long-term exposure to hypertonic glucose 9.

The development of animal models has provided rationale for other therapeutic strategies against structural and functional alterations of the PM. Inhibition of the formation of AGEs with compounds such as aminoguanidine or OPB are being currently evaluated, as well as the possibility of detoxifying RCOs by the glyoxalase pathway Inhibition of the L-arginine: NO pathway, for instance with L-arginine analogues, has been shown to dramatically improve UF in rat model of acute peritonitis 16, but the clinical application of such compounds is currently limited by lack of specificity Modulation of angiogenesis with agents that inhibit endothelial cell growth, adhesion or migration, or interfere with growth factors and their receptors have been proposed Recently, adenovirus-mediated gene transfer of the endogenous inhibitor angiostatin was shown to improve structural and functional parameters in a chronic infusion rat model However, it should be kept in mind that i different molecular pathways are probably involved in cancerous vs non-cancerous angiogenesis; ii angiogenic growth factors may participate in other physiological processes; iii there is little information on safety, longterm side-effects, and impact of antiangiogenic therapy on processes such as healing The pharmacologic induction of AQP1 may also provide a target for manipulating water permeability across the PM and treating some cases of UF failure Finally, a better knowledge of the molecular mechanisms operating in the PM will probably allow to identify genetic determinants involved in the individual variability of the PM permeability at the onset of PD.

Supplementary files

The author wishes to thank Drs. Gillerot, E.

Protein transport into nucleus

Goffin, R. Krediet, N. Lameire, and T.

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Miyata for helpful discussions. Krediet RT: The peritoneal membrane in chronic peritoneal dialysis. Kidney Int , J Am Soc Nephrol 9: , Pathophysiological implications for the classification of peritoneal membrane alterations. Nephrol Dial Transplant , Am J Kidney Dis , Flessner M: Changes in the peritoneal interstitium and their effect on peritoneal transport. Perit Dial Int SS82, Nephrol Dial Transplant 17 Supl. J Am Soc Nephrol , Dobbie JW: New concepts in molecular biology and ultrastructural pathology of the peritoneum: their significance for peritoneal dialysis.

Nephron , Perit Dial Int , Peritoneal biopsiy Study Group: morphologic changes in the peritoneal membrane of patients with renal disease. Miyata T, Kurokawa K, van Ypersele de Strihou C: Advanced glycation and lipoxidation end products: role of reactive carbonyl compounds generated during carbohydrate and lipid metabolism.

Membrane Biology and Protein Trafficking

Inagi R, Miyata T, Yamamoto T, Suzuki D, Urakami K, Saito A, van Ypersele de Strihou C, Kurokawa K: Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis.

FEBS Lett , Annu Rev Biochem , Endocrine Rev , Ferrara N: Role of vascular endothelial growth factor in the regulation of angiogenesis. Kubes P: Nitric oxide affects microvascular permeability in the intact and inflamed vasculature. Microcirculation 2: , Am J Physiol HH, Miyata T, Devuyst O, Kurokawa K, van Ypersele de Strihou C: Advances in the biochemistry and pathophysiology of the peritoneal membrane: new therapeutic insights into more biocompatible peritoneal dialysis.

Prior to the introduction of modern loop diuretics, patients with refractory fluid overload were treated with calomel mercurous chloride oxidizes to mercuric chloride which delivers profound renal diuresis. An isolated water molecule is believed to transiently form partial hydrogen bonds with both asparagines, thus undergoing a temporary dipole reorientation of the water molecule.

After further descent through the channel, an isolated water molecule then interacts with a second string of carbonyl oxygens L75, H74, A73, G72 on the peptide backbone as they exit the channel into the cytoplasmic vestibule. The presence of relatively few sites where water can interact with the walls of the pore contributes to the rapid speed for the water movement.

These predictions were verified and further delineated by molecular dynamics simulations [ 21 , 22 ]. Interestingly, the orientation of a water molecule changes as it passes through the channel. The oxygen faces down when the water molecule enters from the extracellular side. The water molecule flips when interacting with both asparagines of the NPA motifs, and moves further down the channel with the oxygen facing upwards Fig. This description is written from the perspective of water entering a cell through an aquaporin.

The same molecular events will occur in the reverse order as water is released from a cell through an aquaporin. This reverse flow is equivalently important. In many physiological processes water may enter cells or be released from cells. In the case of polarized epithelia, water enters at one surface of the cell and is released from the other surface.

Eleven mammalian aquaporins have now been identified and at least partially characterized Fig. These conform to two subsets of proteins — those selectively permeated by water classic aquaporins and those permeated by water plus glycerol aquaglyceroporins.

This is an oversimplification, since AQP0 and AQP6 have been found to exhibit biophysical functions different from water or glycerol transport. The atomic structure of the aquaglyceroporin GlpF has been solved [ 18 ] , and transport of glycerol through the channel has been simulated by molecular dynamics [ 22 ]. The detailed mechanism by which glycerol is transported by aquaglyceroporins will be presented in the minireview in this issue by R.

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In many cases, the sites of expression predict physiological and pathological roles. The mammalian homologs are expressed in specific tissues, but it should be noted that aquaporins are not expressed in all cell types. For example, no aquaporin has been identified in neurons. Moreover, the developmental expression of aquaporins is often complex.

For example, AQP1 is expressed in rat renal tubules only after birth but not before [ 24 ]. In cells expressing more than one aquaporin, the different homologs usually reside in different membranes. For example, in salivary glands, AQP3 is present in basolateral membranes where water is taken up from the interstitium, and AQP5 resides in the apical membrane where water is released during salivation [ 26 ].

Aquaporins have been identified in numerous tissues, and the importance of these proteins in several disease states is becoming clear. In some instances, the structure of the proteins provides detailed understanding into the molecular mechanisms for protein dysfunction. In other instances, the subcellular localization of the protein provides obvious clues.

Examples of each are illustrated below.

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  • AQP1 is extremely abundant in both apical and basolateral membranes of renal proximal tubules and in capillary endothelium [ 27 ]. Exceedingly rare humans lack the Co blood group antigen, a specific extracellular domain of AQP1 protein [ 28 ]. Capillary water permeability was measured in a second study.

    The final stages of urinary concentration occur in the renal collecting ducts. In the diuretic state, AQP2 resides in intracellular vesicles in principal cells where the location prevents reabsorption of water from the glomerular filtrate [ 32 , 33 ]. This is well recognized in our everyday lives, since intake of excessive fluid or inhibition of vasopressin release from the central nervous system by alcohol or caffeine causes our kidneys to secrete large volumes of dilute urine.

    Individuals with mutations in the gene encoding AQP2 suffer from a severe form of nephrogenic diabetes insipidus NDI and release up to 20 l of urine per day [ 34 ].

    Annual Meeting: What’s New In Membrane Transport Proteins

    Secondary reductions in AQP2 expression have also been identified in other polyuric states, including enuresis. In normal individuals, release of vasopressin causes the AQP2 proteins to become exocytosed into the apical plasma membrane, permitting water reabsorption from filtrate. If too much AQP2 protein is expressed, water reabsorption may become excessive, and this is believed to contribute to common fluid overload states found in patients with congestive heart failure or pregnancy see review [ 35 ].

    The mechanisms by which kidneys control urine acidification are less well defined but are likely to involve AQP6. AQP0 also known as major intrinsic protein is expressed in ocular lens fiber cells [ 40 ]. Lenses are avascular and anuclear. To maintain transparency, fiber cells must remain viable throughout life. Lens is not a tissue with high water permeability. Inherited defects in the gene encoding AQP0 have been identified in two large kindreds with dominantly inherited cataracts affecting small children [ 43 ]. Interestingly, the mutations occur in highly conserved residues believed to be critical to the protein structure [ 44 ].

    All affected members of the EG family suffer from lamellar opacities corresponding to the perimeter of the lens at birth. The substitution TR will form an ion pair with E, thereby perturbing the architecture of the aqueous pore. Unlike the EG family, all members of the family with the TR mutation suffer from polymorphic opacities throughout the lens due to deposition of protein throughout childhood and adult life.

    Identification of major perturbations to AQP0 structure in families with severe, congenital cataracts suggests that more subtle polymorphisms in AQP0 may be a risk factor contributing to precipitation of cataracts that are much more commonly found in older individuals.