ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of ReviewFabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A. The lack of enzyme activity results in an intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide, in various tissues. Significant morbidity is caused by progressive effects on the vascular endothelium, heart, brain and kidney leading to end-stage renal disease. In this review we would like to give a current overview on recent advances in therapy and an outlook on future aspects in the management of Fabry disease.Recent findingsBesides symptomatic management, enzyme replacement therapy with recombinant α-galactosidase A is the only specific treatment currently available. Clinical trials using recombinant α-galactosidase A showed safety and efficacy in reversing substrate storage in different tissues. Short-term response on clinical manifestations such as impaired kidney function demonstrates a clear potential to improve and stabilize symptoms of the disease. In patients with residual enzyme activity enzyme enhancement therapy with pharmacological chaperones seems to be an attractive approach. Enzyme replacement therapy mediated by gene transfer may become a promising alternative treatment strategy in the future.SummaryRemarkable advances in the treatment of patients with Fabry disease have been made with the introduction of enzyme replacement therapy in clinical use. Although lysosomal globotriaosylceramide deposits are cleared very effectively, longer term experience on clinical outcome in patients with severe vital organ involvement is still limited.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThis review will examine the most recent evidence that adenosine receptors in the kidney can alter kidney function. Adenosine A1-receptors located in the afferent arteriole and proximal tubule can contribute to fluid retaining disorders by mediating tubuloglomerular feedback, afferent arteriole vasoconstriction or direct sodium absorption. In addition, A1-receptors may have a role for the prevention or treatment of ischemic injury to the kidney by maintaining afferent arteriole vasodilatation and preserving the glomerular filtration rate.Recent findingsAnimal and human studies confirm that adenosine A1-receptor antagonists are useful adjuvants to the treatment of congestive heart failure by increasing diuresis and natriuresis and preserving the glomerular filtration rate. These agents most likely function to directly inhibit tubular absorption of sodium, as well as inhibit tubuloglomerular feedback. There is increasing evidence that adenosine A1-receptors directly affect the release of renin, and that adenosine and angiotensin II act synergistically to increase renal vascular resistance and decrease renal blood flow. The ability of adenosine A1-receptor antagonists to preserve the glomerular filtration rate and protect the kidney against ischemic damage or drug toxicity is not well established.SummaryThe utility of adenosine A1-receptor antagonists in the treatment of congestive heart failure should lead to larger clinical trials of these agents. There is increasing evidence that the receptors mediate vasoconstriction that is unique to the renal microcirculation. However, studies of adenosine A1-receptor antagonists in animal models have largely been unsuccessful in preventing ischemic kidney damage, most likely due to the diversity of factors and events that are involved.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe goal of this article is to review the physiology and describe newly defined molecular mechanisms that are responsible for renal urate transport.Recent findingsFour complementary DNAs have recently been cloned whose expressed proteins transport urate. Two of these proteins have been localized to the apical membrane of proximal tubular cells: one, a urate transporter/channel, a galectin, is an electrogenic transporter (an ion channel); the second is a urate-anion electroneutral exchanger, a member of the organic anion transporter family. The other urate transport proteins, organic anion transporters 1 and 3, are also members of the organic anion transporter family. These proteins have been localized to the basolateral membrane of proximal tubular cells: organic anion transporter 1 is an electroneutral organic anion exchanger; the mechanism of urate transport on organic anion transporter 3 remains to be determined.SummaryThe molecular definition and localization of four urate transport proteins provides a basis for developing a molecular model of the bi-directional transport of urate in renal proximal tubules. It seems likely that the urate-anion exchanger is responsible for luminal reabsorption while the urate transporter/channel permits secretion of urate from the cell into the lumen. Since organic anion transporters 1 and 3 reside in the basolateral membrane, one or both may be relevant in the reabsorptive flux of urate into the peritubular capillary as well as in the cellular uptake of urate from the peritubular space, the first step in the process of urate secretion. Knowledge of the molecular basis of urate transport should provide greater insights into states of altered transport as well as assist in development of drugs to modify urate flux.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewTo discuss recent reports on the function and importance of the renal primary cilium, a widely distributed organelle.Recent findingsMost epithelial cells, including those in the kidney, express a solitary primary cilium. The primary cilium functions as a flow sensor in cultured renal epithelial cells (MDCK and mouse collecting tubule) mediating a large increase in intracellular calcium concentration. Flow sensing is shown to reside in the cilium itself and to involve the proteins polycystin 1 and 2, defects in which are associated with the majority of cases of human polycystic kidney disease. The role of the cilium in flow-dependent potassium secretion by the collecting tubule and in sensing of chemical components of the luminal fluid are also described.SummaryThe primary cilium is mechanically sensitive and serves as a flow sensor in cultured renal epithelia. Bending the cilium by mechanical means or flow causes a large, prolonged transient increase in intracellular calcium. The mechanically sensitive protein in the cilium is a polycystin.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThis review examines the maturational changes that occur in renal tubules during postnatal development.Recent findingsThe ability to study transport in neonatal tubules and the use of molecular techniques have allowed studies that not only examine the mechanism of solute and water transport in neonates but also what causes the maturational changes in transport at a molecular and cellular level.SummaryThis review demonstrates that there are significant quantitative and qualitative differences in transport during postnatal maturation in every nephron segment. In some segments the maturational changes involve simply a change in abundance of transporters, while in others the difference in transport is due to changes in transporter isoforms, changes in paracellular permeability or changes in intracellular signaling that regulate the transporter. This review focuses on these changes and what is known about what causes the maturational changes in transport.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThis review describes recent advances in our understanding of the genetic heterogeneity, pathophysiology and treatment of Bartter syndrome, a group of autosomal recessive disorders that are characterized by markedly reduced or absent salt transport by the thick ascending limb of Henle. Consequently, individuals with Bartter syndrome exhibit renal salt wasting and lowered blood pressure, hypokalemic metabolic alkalosis and hypercalciuria with a variable risk of renal stones.Recent findingsPreviously, three genes (SLC12A2, the sodium-potassium-chloride co-transporter;KCNJ1, the ROMK potassium ion channel;ClC-Kb, the basolateral chloride ion channel) had been identified as causing antenatal and ‘classic’ Bartter syndrome. Two additional genes have now been identified. Barttin is a β-subunit that is required for the trafficking of CLC-K (both ClC-Ka and ClC-Kb) channels to the plasma membrane in both the thick ascending limb and the marginal cells in the scala media of the inner ear that secrete potassium ion-rich endolymph. Loss-of-function mutations in barttin thus cause Bartter syndrome with sensorineural deafness. In addition, severe gain-of-function mutations in the extracellular calcium ion-sensing receptor can result in a Bartter phenotype because activation of this G protein-coupled receptor inhibits salt transport in the thick ascending limb (a furosemide-like effect).SummaryFive genes have been identified as causing Bartter syndrome (types I-V), with the unifying pathophysiology being the loss of salt transport by the thick ascending limb. Phenotypic differences in Bartter types I-V relate to the specific physiological roles of the individual genes in the kidney and other organ systems.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe proximal tubule sodium/hydrogen exchanger continuously reabsorbs the bulk of the filtered sodium, controlling salt delivery to the distal nephron which is critical for tubuloglomerular feedback autoregulation and for fine control of salt excretion in the distal nephron. This review focuses on recent studies of the mechanisms of regulation of sodium transport in the proximal tubule, and addresses whether results from studies in proximal tubule cell lines are applicable to the proximal tubulein situ.Recent findingsRecent in-vivo studies provided evidence that sodium/hydrogen exchanger isoform 3 can move into and out of the apical microvilli accompanied by parallel changes in renal sodium transport: the exchanger is retracted from the microvilli in response to hypertension, parathyroid hormone or dopamine treatment and moved into the microvilli in response to sympathetic nervous system stimulation, puromycin aminonucleoside induced nephritic syndrome, and insulin treatment. Studies in cultured opossum kidney proximal tubule cells provided evidence for clathrin coated vesicle mediated, dynamin dependent, cytoskeleton dependent internalization of sodium/hydrogen exchanger isoform 3 from the surface to an endosomal pool in response to dopamine or parathyroid hormone. In the intact proximal tubule there is evidence for a two-step internalization process: (1) from villi to the intermicrovillar cleft region and (2) to a higher density membrane pool that may be either below the microvilli or deep in intermicrovillar clefts. Recent studies have described a significant inactive pool of the exchanger in the intermicrovillar regionin vivothat may serve as a storage and recruitable pool.SummaryThe molecular mechanisms responsible for increasing or decreasing sodium transport in the proximal tubule appear to include redistribution of sodium/hydrogen exchanger isoform 3 to or from the microvillar region. Detailed studies in cultured proximal tubule cell lines provide evidence for endocytosis and exocytosis of the exchanger dependent on cytoskeleton and clathrin coated vesicles.In vivo,the apical membrane is differentiated into discrete villar and intermicrovillar membrane domains and the intermicrovillar domain, not observed in cultured cells, may serve as a recruitable storage pool for sodium/hydrogen exchanger isoform 3.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe case is made that tight junctions can undergo large reversible conductance changes in a matter of seconds and yet preserve their permselectivity. The diuretic peptide leucokinin transforms (renal) Malpighian tubules of the yellow fever mosquito from a moderately tight epithelium to a leaky epithelium by increasing the chloride-conductance of the paracellular shunt pathway. The nine-fold increase in the paracellular chloride-conductance brings about a non-selective stimulation of transepithelial sodium chloride and potassium chloride secretion, as expected from a conductance increase in the pathway taken by the counterion of sodium and potassium.Recent findingsThe leucokinin signaling pathway consists in part of a receptor coupled G-protein, phospholipase C, inositol-1,4,5-trisphosphate, and increased intracellular calcium concentration that bring about the increase in the paracellular, tight junction chloride-conductance. As the conductance of the tight junction pathway increases it becomes more selective for the transepithelial passage of chloride.SummaryEpithelial cells in Malpighian tubules taper to tight junctions at their lateral edges exposing them directly to apical and serosal solutions. Furthermore, evolutionary pressures to excrete salt and water at high rates without the aid of glomerular filtration have led to powerful mechanisms of tubular secretion, capable of diuresis when the mosquito is challenged with the volume expansion of a blood meal. The tubular diuresis is mediated in part by increasing the paracellular chloride conductance. Thus, anatomical and physiological specializations in Malpighian tubules combine to yield the evidence for the dynamic hormonal regulation of the tight junction pathway.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID