Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats

Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats. It has become widely recognized that glycine (Gly) depletion predisposes isolated proximal tubules (PT) to necrotic cell damage induced by diverse insults and that Gly replacement in vitro is highly cytoprotective. However, the effectiveness of supplementation with Gly in vivo, where blood and tissue Gly normally are maintained at high levels, is incompletely defined. Our aim was to assess whether: (a) supplementation of Gly in drinking water of rats would attenuate the proximal tubule damage and the Fanconi syndrome (FS) induced by maleate (Mal), a classical proximal tubule toxin, or ifosfamide (IFO), an antineoplastic drug; and (b) to explore the mechanisms responsible for such effects, since Gly supplementation might be especially beneficial in treating the FS, where the kidney tends to waste amino acids. Rats received daily injection of Mal (2 mmol/kg) for two days without or with oral supplementation of 2% Gly. IFO, 50 mg/kg, was injected daily for five days without or with oral Gly. Control rats were injected with saline, without or with oral Gly. The results demonstrated that both Mal and IFO induced a FS characterized by wasting of amino and organic acids, glucose, and electrolytes, along with elevated plasma creatinine (Crn) and BUN, and decreased Crn clearance rate. Light microscopy revealed a necrotic lesion in the proximal tubules of the Mal group, but no necrosis after IFO. Gly strongly ameliorated the severity of renal necrosis and/or dysfunction induced by Mal or IFO, with significant decreases in total and fractional excretion of Na+, K+, PO43− and glucose, decreased plasma BUN and Crn, and increased Crn clearance. Analysis of freeze-clamped cortical tissue showed substantial depletion of [Gly], [ATP] and [GSH] along with increased GSSG in Mal or IFO groups and correction of [Gly] and [ATP] with Gly supplementation, but no improvement with Gly of reduced gluthatione [GSH] or the ratio of reduced to oxidized gluthatione (GSH/GSSG). 31P-NMR analysis of the renal cortex indicated a decrease in Pi and various membrane phospholipids in Mal and IFO rats and prevention of this damage with Gly. These observations demonstrate that oral supplementation of Gly can provide protection against Mal or IFO-induced renal tubular cell dysfunction and structural damage. The lack of effect on glutathione oxidation and depletion suggests an action distal to toxin uptake and intracellular interactions, which is similar to the characteristics of Gly cytoprotection against diverse insults in vitro. The results also suggest modification by Gly of the primary toxicity of the agents and effects on phospholipid synthesis that could contribute to repair

A Gravity Dual and LHC Study of Single-Sector Supersymmetry Breaking

We propose a gravitational dual of ``single-sector'' models of supersymmetry breaking which contain no messenger sector and naturally explain the scale of supersymmetry breaking and the fermion mass hierarchy. In five dimensions these models can be given a simple interpretation. Inspired by flux-background solutions of type IIB supergravity, a metric background that deviates from AdS_5 in the IR breaks supersymmetry, while the fermion mass hierarchy results from the wavefunction overlap of bulk fermions with a UV-confined Higgs field. The first and second generation squarks and sleptons, which are localized near the IR brane, directly feel the supersymmetry breaking and obtain masses of order 10 TeV. These are interpreted as composite states of the dual 4D theory. The gauginos and third generation squarks and sleptons are elementary states that obtain soft masses of order 1 TeV at the loop level via direct gauge mediation. This particle spectrum leads to distinctive signatures at the LHC, similar to the usual gauge mediation with a neutralino NLSP that decays promptly to a gravitino LSP, but with lower event rates. Nevertheless we show that with 1-10 fb^{-1} of LHC data "single-sector" models can easily be detected above background and distinguished from conventional gravity and gauge mediation.Comment: 35 pages, 6 figures, LaTe

Adenine nucleotide metabolism by isolated kidney tubules during oxygen deprivation

Suspensions enriched in isolated rabbit proximal tubules were subjected to varying degrees of oxygen deprivation-induced injury by incubating them under hypoxic conditions at pH 7.4 or pH 6.6 or under high density pelleted conditions and adenine nucleotide degradation was characterized. The major metabolite was hypoxanthine. Its levels increased with the extent of irreversible injury. It was not further degraded or salvaged. Recovery of cell ATP during reoxygenation was predominantly from the remaining cell nucleotides. Allopurinol did not alter the pattern of purine metabolism or the extent of cell injury. These observations provide information on the intrinsic purine metabolic capacity of renal tubule cells during oxygen deprivation which is relevant to understanding both the salvage mechanisms available in these cells as well as the contribution of purine metabolism to the pathogenesis of oxygen deprivation-induced tubule cell injury.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27280/1/0000296.pd

Structural requirements for protection by small amino acids against hypoxic injury in kidney proximal tubules1

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154313/1/fsb2004015011.pd

Distribution of gentamicin among subcellular fractions from rat renal cortex

A substantial amount of data is available to suggest that lysosomal sequestration of amino-glycoside antibiotics plays a role in the pathogenesis of aminoglycoside induced renal tubule cell injury; however, relatively little information is available on the subcellular distribution of Aminoglycosides in the kidney during treatment protocols of the type that ultimately go on to produce extensive lethal renal tubule cell injury and acute renal failure in experimental animals. This study assessed the distribution of gentamicin and subcellular membranes on a discontinuous sucrose density gradient after in vivo exposure of rats to four daily 100 mg/kg doses of gentamicin as compared to in vitro exposure of normal rat renal cortex to gentamicin during tissue homogenization at drug levels comparable to those seen after in vivo treatment. After both in vivo and in vitro exposure, major localization of gentamicin, the lysosomal marker enzyme (NAG), and the endoplasmic reticulum marker enzyme NADPH-cytochrome c reductase, occurred in a very light membrane fraction. Within this membrane fraction, gentamicin was more closely associated with the NAG than with the NADPH-cytochrome c reductase. The results could not be explained by complete lysosomal disruption during subcellular fractionation after in vivo gentamicin. These data provide additional insights into both the possibilities for subcellular interactions of aminoglycosides in the kidney, and into the methodology required to optimally assess such interactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25665/1/0000217.pd

Calcium compartmentation in isolated renal tubules in suspension

Substantial increases of total cell Ca2+ have been observed in suspensions of isolated rabbit proximal tubules subjected to hypoxic injury or treated with exogenous ATP followed by apparent recovery with reoxygenation of the hypoxic tubules or continued incubation of ATP-treated tubules. Ca2+ compartmentation studies using digitonin and metabolic inhibitors were done to clarify the basis for these changes. Digitonin, 40-90 [mu]g/mg tubule protein, rapidly permeabilized the tubule cells and did not impair mitochondrial Ca2+ sequestration. Most of the increases of tubule cell Ca2+ produced by hypoxia and ATP were accounted for by pools which could be rapidly removed by exposure of tubules to EGTA and the uncoupler carbonyl cyanide m-chlorophenyl hydrazone without concomitant use of digitonin, suggesting that the changes of Ca2+ predominantly reflect sequestration by mitochondria in severely damaged cells or mitochondria already released to the medium from them. The time course of uptake followed by spontaneous release of mitochondrial Ca2+ from tubule cells deliberately permeabilized with digitonin, then incubated for prolonged periods, indicated that the decreases of tubule cell Ca2+ during reoxygenation of hypoxic suspensions and prolonged incubation of ATP-treated tubules were likely to be attributable to loss of Ca2+ from free mitochondria and those in damaged cells rather than to extrusion by intact cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27353/1/0000378.pd

Glycine Protection of PC-12 Cells Against Injury by ATP-Depletion

A distinctive mechanism of cell injury during ATP depletion involves the loss of cellular glycine. The current study examined whether provision of glycine during ATP depletion can prevent injury in PC-12 cells, a cell line with neuronal property. In addition, we have examined the role played by glycine receptors in cytoprotective effects of the amino acid. It was shown that ATP depletion led to plasma membrane damage in PC-12 cells, which was ameliorated by 0.25–5mM glycine. Cytoprotective activity of glycine was shared by alanine, but not by glutamate or γ-aminobutyric acid (GABA). Of interest, strychnine, an antagonist of glycine receptor, was also protective. The results, while suggesting the involvement of glycine receptor in cytoprotection, indicate that chloride channel activity of the receptor is dispensable. Such a scenario is further supported by the observation that removal of extracellular chloride did not affect ATP depletion–induced cell injury or its prevention by glycine. In short, this study has provided the first evidence for glycine protection of cells with neuronal properties. Cytoprotection may involve the glycine receptor; however, it can be dissociated from its channel activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45423/1/11064_2004_Article_462865.pd

Defining the Force between Separated Sources on a Light Front

The Newtonian character of gauge theories on a light front requires that the longitudinal momentum P^+, which plays the role of Newtonian mass, be conserved. This requirement conflicts with the standard definition of the force between two sources in terms of the minimal energy of quantum gauge fields in the presence of a quark and anti-quark pinned to points separated by a distance R. We propose that, on a light front, the force be defined by minimizing the energy of gauge fields in the presence of a quark and an anti-quark pinned to lines (1-branes) oriented in the longitudinal direction singled out by the light front and separated by a transverse distance R. Such sources will have a limited 1+1 dimensional dynamics. We study this proposal for weak coupling gauge theories by showing how it leads to the Coulomb force law. For QCD we also show how asymptotic freedom emerges by evaluating the S-matrix through one loop for the scattering of a particle in the N_c representation of color SU(N_c) on a 1-brane by a particle in the \bar N_c representation of color on a parallel 1-brane separated from the first by a distance R<<1/Lambda_{QCD}. Potential applications to the problem of confinement on a light front are discussed.Comment: LaTeX, 15 pages, 12 figures; minor typos corrected; numerical correction in equation 3.

Spontaneous Symmetry Breaking at Infinite Momentum without P+ Zero-Modes

The nonrelativistic interpretation of quantum field theory achieved by quantization in an infinite momentum frame is spoiled by the inclusion of a mode of the field carrying p+=0. We therefore explore the viability of doing without such a mode in the context of spontaneous symmetry breaking (SSB), where its presence would seem to be most needed. We show that the physics of SSB in scalar quantum field theory in 1+1 space-time dimensions is accurately described without a zero-mode.Comment: LaTeX, 8 pages, 3 eps figure