Showing papers in "American Journal of Physiology-renal Physiology in 2000"
TL;DR: Evidence for possible movement of ions and carbon dioxide through the aquaporins is reviewed here, as well as evidence for direct regulation of aquaporin function by posttranslational modification such as phosphorylation.
Abstract: The aquaporins (AQPs) are a family of small membrane-spanning proteins (monomer size ∼30 kDa) that are expressed at plasma membranes in many cells types involved in fluid transport. This review is ...
645 citations
TL;DR: The recent demonstration that TASK-1 and TREk-1 channels are activated by inhalational general anesthetics, and that TRAAK is activated by the neuroprotective agent riluzole, indicates that this novel class of K(+) channels is an interesting target for new therapeutic developments.
Abstract: The two-pore-domain K+ channels, or K2P channels, constitute a novel class of K+channel subunits. They have four transmembrane segments and are active as dimers. The tissue distribution of these ch...
574 citations
TL;DR: This analysis suggests that the high GFR in very obese subjects may be the result of an increase in transcapillary hydraulic pressure difference (DeltaP), an abnormal transmission of increased arterial pressure to the glomerular capillaries through a dilated afferent arteriole could account for the augmentation in DeltaP.
Abstract: Differential solute clearances were used to characterize glomerular function in 12 nondiabetic subjects with severe obesity (body mass index >38). Nine healthy subjects served as the control group....
540 citations
TL;DR: The present review focuses on the potential physiological regulations involving different isoforms of adenylyl cyclase (AC), the enzymatic activity responsible for the synthesis of cAMP from ATP, emphasizing the role of Ca(2+)/calmodulin in activating AC1 and AC8 in the central nervous system, the potential inhibitory effect ofCa(2+) on AC5 and AC6, and the changes in the expression pattern of the isoforms during development.
Abstract: The present review focuses on the potential physiological regulations involving different isoforms of adenylyl cyclase (AC), the enzymatic activity responsible for the synthesis of cAMP from ATP. Depending on the properties and the relative level of the isoforms expressed in a tissue or a cell type at a specific time, extracellular signals received by the G protein-coupled receptors can be differently integrated. We report here on various aspects of such regulations, emphasizing the role of Ca2+/calmodulin in activating AC1 and AC8 in the central nervous system, the potential inhibitory effect of Ca2+ on AC5 and AC6, and the changes in the expression pattern of the isoforms during development. A particular emphasis is given to the role of cAMP during drug dependence. Present experimental limitations are also underlined (pitfalls in the interpretation of cellular transfection, scarcity of the invalidation models, and so on).
403 citations
TL;DR: Data suggest that T lymphocytes can mediate experimental renal IRI, and adhesion of infiltrating T cells to renal tubular cells may provide a potential mechanism underlying postischemic tubular dysfunction.
Abstract: Mononuclear cell infiltrates are found in human renal ischemia-reperfusion injury (IRI), and peritubular T lymphocytes have been identified in experimental IRI. However, the role of T cells in the ...
339 citations
TL;DR: The mammalian urinary bladder epithelium (urothelium) performs the important function of storing urine for extended periods, while maintaining the urine composition similar to that delivered by the kidneys, which is illustrated by infectious cystitis.
Abstract: The mammalian urinary bladder epithelium (urothelium) performs the important function of storing urine for extended periods, while maintaining the urine composition similar to that delivered by the kidneys. The urothelium possesses four properties to perform this function. First, it offers a minimum epithelial surface area-to-urine volume; this reduces the surface area for passive movement of substances between lumen and blood. Second, the passive permeability of the apical membrane and tight junctions is very low to electrolytes and nonelectrolytes. Third, the urothelium has a hormonally regulated sodium absorptive system; thus passive movement of sodium from blood to urine is countered by active sodium reabsorption. Last, the permeability properties of the apical membrane and tight junctions of the urothelium are not altered by most substances found in the urine or blood. The importance of the barrier function of the urothelium is illustrated by infectious cystitis. The loss of the barrier function results in the movement of urinary constituents into the lamina propria and underlying muscle layers, resulting in suprapubic and lower back pain and frequent, urgent, and painful voiding.
323 citations
TL;DR: In vitro studies in human renal proximal tubule cells demonstrate that hemin, an inducer of HO-1, significantly attenuated cisplatin-induced apoptosis and necrosis, whereas inhibition ofHO-1 enzyme activity reversed the cytoprotective effect.
Abstract: Heme oxygenase-1 (HO-1) is a 32-kDa microsomal enzyme that catalyzes the conversion of heme to biliverdin, releasing iron and carbon monoxide. Induction of HO-1 occurs as a protective response in cells/tissues exposed to a wide variety of oxidant stimuli. The chemotherapeutic effects of cis-diamminedichloroplatinum(II) (cisplatin), a commonly used anticancer drug, are limited by significant nephrotoxicity, which is characterized by varying degrees of renal tubular apoptosis and necrosis. The purpose of this study was to evaluate the functional significance of HO-1 expression in cisplatin-induced renal injury. Our studies demonstrate that transgenic mice deficient in HO-1 (-/-), develop more severe renal failure and have significantly greater renal injury compared with wild-type (+/+) mice treated with cisplatin. In vitro studies in human renal proximal tubule cells demonstrate that hemin, an inducer of HO-1, significantly attenuated cisplatin-induced apoptosis and necrosis, whereas inhibition of HO-1 enzyme activity reversed the cytoprotective effect. Overexpression of HO-1 resulted in a significant reduction in cisplatin-induced cytotoxicity. These studies provide a basis for future studies using targeted gene expression of HO-1 as a therapeutic and preventive modality in high-risk settings of acute renal failure.
316 citations
TL;DR: The capacity of PGE( 2) to bidirectionally modulate vascular tone and epithelial transport via constrictor EP(1) and EP(3) receptors vs. dilator EP(2) andEP(4) receptors allows PGE (2) to serve as a buffer, preventing excessive responses to physiological perturbations.
Abstract: Prostaglandin E2 is a major renal cyclooxygenase metabolite of arachidonate and interacts with four G protein-coupled E-prostanoid receptors designated EP1, EP2, EP3, and EP4. Through these recepto...
289 citations
TL;DR: Comparison of the structurally closely related OATs and OCTs may be possible to delineate the binding sites for organic anions and cations in future experiments, as well as demonstrate polyspecificity of the Oats, OCTs, and OCTN1.
Abstract: Here we review the structural and functional properties of organic anion transporters (OAT1, OAT2, OAT3) and organic cation transporters (OCTN1, OCTN2, OCT1, OCT2, OCT3), some of which are involved...
279 citations
TL;DR: A commonly accepted hypothesis is that a chronically high-sodium diet expands extracellular volume and finally reaches a steady state where sodium intake and output are balanced whereas extracellul...
Abstract: A commonly accepted hypothesis is that a chronically high-sodium diet expands extracellular volume and finally reaches a steady state where sodium intake and output are balanced whereas extracellul...
263 citations
TL;DR: It is demonstrated for the first time that rat kidneys can be preconditioned to attenuate isChemic-reperfusion injury and adenosine infusion before ischemic insult protects renal function via A(1) adenosin receptor activation.
Abstract: Renal ischemia and reperfusion during aortic and renal transplant surgery result in ischemic-reperfusion injury. Ischemic preconditioning and adenosine infusion before ischemia protect against isch...
TL;DR: This review aims to evaluate the relevance and utility of the experimental models currently available to study ischemic and toxic renal injury, to suggest novel experimental approaches and models that have the potential to provide advantages over methods currently available and to discuss the difficulties inherent in clinical studies of ATN.
Abstract: Acute renal failure (ARF) due to ischemic1 or toxic renal injury, a clinical syndrome traditionally referred to as acute tubular necrosis (ATN), is a common disease with a high overall mortality of...
TL;DR: When a critical renal developmental morphogen, osteogenic protein-1 (OP-1) is administered at the time of UUO and every other day thereafter, interstitial inflammation and fibrogenesis are prevented, leading to preservation of renal function during the first 5 days after obstruction.
Abstract: Unilateral ureteral obstruction (UUO) is a model of renal injury characterized by progressive tubulointerstitial fibrosis and renal damage, while relatively sparing the glomerulus and not producing...
TL;DR: Electrochemical detection of NO release from cultured endothelial cells demonstrated that concentrations of Hcy >20 microM produce a significant indirect suppression of eNOS activity without any discernible effects on its expression, suggesting that cellular redox state plays an important role in HCy-suppressed NO-generating function of this enzyme.
Abstract: Hyperhomocysteinemia (HHCy) is an independent and graded cardiovascular risk factor. HHCy is prevalent in patients with chronic renal failure, contributing to the increased mortality rate. Controversy exists as to the effects of HHCy on nitric oxide (NO) production: it has been shown that HHCy both increases and suppresses it. We addressed this problem by using amperometric electrochemical NO detection with a porphyrinic microelectrode to study responses of endothelial cells incubated with homocysteine (Hcy) to the stimulation with bradykinin, calcium ionophore, or l-arginine. Twenty-four-hour preincubation with Hcy (10, 20, and 50 μM) resulted in a gradual decline in responsiveness of endothelial cells to the above stimuli. Hcy did not affect the expression of endothelial nitric oxide synthase (eNOS), but it stimulated formation of superoxide anions, as judged by fluorescence of dichlorofluorescein, and peroxynitrite, as detected by using immunoprecipitation and immunoblotting of proteins modified by tyr...
TL;DR: All three subunits of ENaC are upregulated by vasopressin with temporal and regional differences, but changes are too slow to play a major role in the short-term action of vasoppressin to stimulate sodium reabsorption in the collecting duct.
Abstract: Sodium transport is increased by vasopressin in the cortical collecting ducts of rats and rabbits. Here we investigate, by quantitative immunoblotting, the effects of vasopressin on abundances of the epithelial sodium channel (ENaC) subunits (alpha, beta, and gamma) in rat kidney. Seven-day infusion of 1-deamino-[8-D-arginine]-vasopressin (dDAVP) to Brattleboro rats markedly increased whole kidney abundances of beta- and gamma-ENaC (to 238% and 288% of vehicle, respectively), whereas alpha-ENaC was more modestly, yet significantly, increased (to 142% of vehicle). Similarly, 7-day water restriction in Sprague-Dawley rats resulted in significantly increased abundances of beta- and gamma- but no significant change in alpha-ENaC. Acute administration of dDAVP (2 nmol) to Brattleboro rats resulted in modest, but significant, increases in abundance for all ENaC subunits, within 1 h. In conclusion, all three subunits of ENaC are upregulated by vasopressin with temporal and regional differences. These changes are too slow to play a major role in the short-term action of vasopressin to stimulate sodium reabsorption in the collecting duct. Long-term increases in ENaC abundance should add to the short-term regulatory mechanisms (undefined in this study) to enhance sodium transport in the renal collecting duct.
TL;DR: The data on mice adapted to moderately low and high Na intake suggest that regulation of ENaC function in vivo involves shifts of beta- and gamma-subunits from the cytoplasm to the apical plasma membrane and vice versa, respectively.
Abstract: Previous electrophysiological experiments on renal cortical collecting ducts indicated that dietary sodium intake and variations in aldosterone plasma levels regulate the abundance of functional ep...
TL;DR: Elevated NaCl and/or urea reduces the number of proliferating mIMCD3 cells by slowing the transit through the S phase, by cell cycle delay in the G(2)M and G(1), and by inducing apoptotic cell death.
Abstract: We investigated the effects of hyperosmolality on survival and proliferation of subconfluent cultures of mIMCD3 mouse renal collecting duct cells. High NaCl and/or urea (but not glycerol) reduces t...
TL;DR: The hypothesis that AGEs cause mesangial oxidative stress and alterations in PKC-beta(II), changes that may ultimately contribute to phenotypic abnormalities associated with diabetic nephropathy are supported.
Abstract: Increased activation of specific protein kinase C (PKC) isoforms and increased nonenzymatic glycation of intracellular and extracellular proteins [the accumulation of advanced glycation end product...
TL;DR: The data suggest that rO CT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.
Abstract: Renal excretion and reabsorption of organic cations are mediated by electrogenic and electroneutral organic cation transporters, which belong to a recently discovered family of polyspecific transporters. These transporters are electrogenic and exhibit differences in substrate specificity. In rat, the renal expression of the polyspecific cation transporters rOCT1 and rOCT2 was investigated. By in situ hybridization, significant amounts of both rOCT1 and rOCT2 mRNA were detected in S1, S2, and S3 segments of proximal tubules. By immunohistochemistry, expression of the rOCT1 protein was mainly observed in S1 and S2 segments of proximal tubules, with lower expression levels in the S3 segments. At variance, rOCT2 protein was mainly expressed in the S2 and S3 segments. Both transporters were localized to the basolateral cell membrane. Neither rOCT1 nor rOCT2 was detected in the vasculature, the glomeruli, and nephron segments other than proximal tubules. The data suggest that rOCT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.
TL;DR: regulation of sgk by aldosterone in native mammalian epithelia and its effect on ENaC are characterized to suggest that the response is mediated, at least in part, by occupancy of the mineralocorticoid receptor.
Abstract: Aldosterone is the major corticosteroid regulating Na+ absorption in tight epithelia and acts primarily by activating the epithelial Na+ channel (ENaC) through unknown induced proteins. Recently, i...
TL;DR: It is demonstrated that AQP2 phosphorylated in Ser(256) is present in the apical plasma membrane and in intracellular vesicles and that both the intrACEllular distribution/trafficking, as well as the abundance of p-AQP2, are regulated via V(2) receptors by altering phosphorylation and/or dephosphorylation of Ser( 256) in AQP1.
Abstract: Phosphorylation of Ser256, in a PKA consensus site, in AQP2 (p-AQP2) appears to be critically involved in the vasopressin-induced trafficking of AQP2. In the present study, affinity-purified antibo...
TL;DR: The recent developments of specific enzymatic inhibitors, stable analogs, and gene-disrupted mice and in antisense technology are enabling investigators to understand the complex interplay by which eicosanoids control renal blood flow.
Abstract: Even though it has been recognized that arachidonic acid metabolites, eicosanoids, play an important role in the control of renal blood flow and glomerular filtration, several key observations have...
TL;DR: Data now show that altering specific cell cycle proteins affects renal cell proliferation and improves renal function and the hope for potential therapeutic interventions is increased.
Abstract: The response to glomerular and tubulointerstitial cell injury in most forms of renal disease includes changes in cell number (proliferation and apoptosis) and cell size (hypertrophy). These events typically precede and may be responsible for the accumulation of extracellular matrix proteins that leads to a decrease in renal function. There is increasing evidence showing that positive (cyclins and cyclin-dependent kinases) and negative (cyclin-dependent kinase inhibitors) cell cycle regulatory proteins have a critical role in regulating these fundamental cellular responses to immune and nonimmune forms of injury. Data now show that altering specific cell cycle proteins affects renal cell proliferation and improves renal function. Equally exciting is the expanding body of literature showing novel biological roles for cell cycle proteins in the regulation of cell hypertrophy and apoptosis. With increasing understanding of the role for cell cycle regulatory proteins in renal disease comes the hope for potential therapeutic interventions.
TL;DR: DWH-146e treatment led to a pronounced decrease in P-selectin- and ICAM-1-like immunoreactivity, consistent with the hypothesis that A(2A)-AR agonists limit I/R injury due to an inhibitory effect on neutrophil adhesion.
Abstract: We sought to determine the mechanisms responsible for the reduced renal tissue injury by agonists of A2A adenosine receptors (A2A-ARs) in models of ischemia-reperfusion (I/R) injury. DWH-146e, a se...
TL;DR: An elastohydrodynamic model is developed to predict the forces and torques along each microvillus and its resulting elastic bending deformation, which indicates that the microvilli, which constitute the brush border, are physically suitable to act as a mechanosensor of fluid flow.
Abstract: In the proximal tubule of the kidney, Na+ and HCO3 − reabsorption vary proportionally with changes in axial flow rate. This feature is a critical component of glomerulotubular balance, but the basi...
TL;DR: TGF responses are enhanced in SHR, in part due to a diminished role for NO from nNOS in blunting TGF due to enhanced O(-)(2) formation.
Abstract: The spontaneously hypertensive rat (SHR) has enhanced tubuloglomerular feedback (TGF) responses and diminished buffering by juxtaglomerular apparatus (JGA)-derived nitric oxide (NO) despite enhance...
TL;DR: It is concluded that OCT3 is expressed in mammalian kidney and that it plays an important role in the renal clearance of cationic drugs.
Abstract: We examined in this study the expression of the potential-sensitive organic cation transporter OCT3 in the kidney. A functionally active OCT3 was cloned from a mouse kidney cDNA library. The cloned transporter was found to be capable of mediating potential-dependent transport of a variety of organic cations including tetraethylammonium. This function was confirmed in two different heterologous expression systems involving mammalian cells and Xenopus laevis oocytes. We have also isolated the mouse OCT3 gene and deduced its structure and organization. The OCT3 gene consists of 11 exons and 10 introns. In situ hybridization studies in the mouse kidney have shown that OCT3 mRNA is expressed primarily in the cortex. The expression is evident in the proximal and distal convoluted tubules. The expression of OCT3 in human kidney was confirmed by RT-PCR. We have also cloned OCT3 from human placenta and human kidney. Human OCT3 exhibits 86% identity with mouse OCT3 in amino acid sequence. Human OCT3 was found to transport tetraethylammonium and a variety of other organic cations. The transport process was electrogenic. We conclude that OCT3 is expressed in mammalian kidney and that it plays an important role in the renal clearance of cationic drugs.
TL;DR: It is anticipated that elucidation of downstream effector signaling mechanisms and a clearer understanding of the immediate and remote upstream activating pathways, when applied to these highly clinically relevant model systems, will ultimately provide much greater insight into the basis for specificity now seemingly absent from these signaling events.
Abstract: Following an overview of the biochemistry of mitogen-activated protein kinase (MAPK) pathways, the relevance of these signaling events to specific models of renal cell function and pathophysiology, both in vitro and in vivo, will be emphasized. In in vitro model systems, events activating the principal MAPK families [extracellular signal-regulated and c-Jun NH2-terminal kinase and p38] have been best characterized in mesangial and tubular epithelial cell culture systems and include peptide mitogens, cytokines, lipid mediators, and physical stressors. Several in vivo models of proliferative or toxic renal injury are also associated with aberrant MAPK regulation. It is anticipated that elucidation of downstream effector signaling mechanisms and a clearer understanding of the immediate and remote upstream activating pathways, when applied to these highly clinically relevant model systems, will ultimately provide much greater insight into the basis for specificity now seemingly absent from these signaling events.
TL;DR: This review summarizes the latest knowledge on molecular and pharmacological properties of renal organic anion transporters and homologs, with special reference to their nephron and plasma membrane localization, transport characteristics, and substrate and inhibitor specificity.
Abstract: Renal organic anion transport systems play an important role in the elimination of drugs, toxic compounds, and their metabolites, many of which are potentially harmful to the body. The renal proxim...
TL;DR: Severe downregulation of AQP2 and AQP3 appears to be important for the development of Li-induced polyuria, while the increased or unchanged expression of NHE3, BSC-1, Na-K-ATPase, and TSC indicates that these Na(+) transporters do not participate in the developmentof Li- induced polyuria.
Abstract: Lithium (Li) treatment is often associated with nephrogenic diabetes insipidus (NDI). The changes in whole kidney expression of aquaporin-1 (AQP1), -2, and -3 as well as Na-K-ATPase, type 3 Na/H ex...