Identification of ABCG2 as an Exporter of Uremic Toxin Indoxyl Sulfate in Mice and as a Crucial Factor Influencing CKD Progression.

Chronic kidney disease (CKD) patients accumulate uremic toxins in the body, potentially require dialysis, and can eventually develop cardiovascular disease. CKD incidence has increased worldwide, and preventing CKD progression is one of the most important goals in clinical treatment. In this study, we conducted a series of in vitro and in vivo experiments and employed a metabolomics approach to investigate CKD. Our results demonstrated that ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a major transporter of the uremic toxin indoxyl sulfate. ABCG2 regulates the pathophysiological excretion of indoxyl sulfate and strongly affects CKD survival rates. Our study is the first to report ABCG2 as a physiological exporter of indoxyl sulfate and identify ABCG2 as a crucial factor influencing CKD progression, consistent with the observed association between ABCG2 function and age of dialysis onset in humans. The above findings provided valuable knowledge on the complex regulatory mechanisms that regulate the transport of uremic toxins in our body and serve as a basis for preventive and individualized treatment of CKD.

Efficacy of benzbromarone in hyperuricemic patients associated with chronic kidney disease.

We have retrospectively evaluated the uric acid control status and renal function changes over a period of up to 7 years in 35 patients with renal impairment who had stage 3 or higher chronic kidney disease (CKD; stage 3 in 32 patients, stage 4 in 2 patients, and stage 5 in 1 patient) associated with hyperuricemia and were receiving monotherapy with benzbromarone as an antihyperuricemic drug. Serum uric acid levels significantly decreased from 8.5 ± 0.9 to 6.1 ± 0.8 mg/dL at 6 months and were subsequently controlled at less than 7.0 mg/dL in most patients. Most patients received benzbromarone at a dose of 25-50 mg/day, whereas 150-200 mg/day was used in some patients with stage 4 or 5 CKD. No significant changes in estimated glomerular filtration rate (eGFR) from the baseline value of 46.2 ± 11.5 mL/minute/1.73 m(2) were found after benzbromarone therapy. Although the renal function impairment did not improve by reducing the serum uric acid levels with benzbromarone, the renal function did not deteriorate further on the therapy. These results suggest that benzbromarone is applicable to the management of hyperuricemia associated with renal impairment.

Actions of cholinergic agonists and antagonists on the efferent synapse in the frog sacculus.

Intracellular recordings were made from hair cells in the frog saccular epithelium isolated with its innervating nerves. Inhibitory post-synaptic potentials (IPSPs) were recorded from hair cells when the efferent fibers were activated by electrical stimulation. The effects of acetylcholine (ACh), cholinomimetics, and cholinergic antagonists on the efferent synapse were studied in a preparation where the IPSPs can be observed directly. ACh or carbachol (CCh) produced a transient membrane hyperpolarization with a decrease in input resistance followed by an abolition or reduction of the IPSP. In a low Ca2+ medium where efferent synaptic activity was abolished, ACh or CCh still induced hyperpolarization, though the response appeared to be smaller than that in normal medium. Neither nicotinic (dimethyl-4-phenyl-piperazinium (DMPP), phenyltrimethylammonium (PTMA) and nicotine) nor muscarinic (muscarine, methacholine, bethanechol and oxotremorine) agonists induced the membrane hyperpolarization, but the former drugs inhibited the IPSPs while the latter drugs did not. Both d-tubocurarine and atropine inhibited the IPSP, but the d-tubocurarine was more potent, causing inhibition even at a dose of 0.5 microM while 2 microM or more atropine was needed. The ACh- or CCh-induced hyperpolarization was inhibited completely by d-tubocurarine (5 microM), but only slightly by atropine (5 microM). These results may indicate that the IPSP and the effects of ACh or CCh are based on a direct interaction between ACh or CCh and ACh receptors on the hair cells.

Effects of activation of the divergent efferent fibers on the spontaneous activity of vestibular afferent fibers in the toad.

In anesthetized toads, spontaneous activities were recorded from single afferent fibers of three semicircular canals and three otolith organs. Since some efferent fibers ramify within the eighth nerve and innervate two or more vestibular organs, a single branchlet of the eighth nerve was disconnected from its end organ, and was electrically stimulated to activate divergent efferent collaterals leading to other vestibular organs. The stimulation elicited an inhibitory effect on spontaneous activities of about one third of the afferent population, and a facilitatory effect on those of another one third. The remaining one third was unaffected. Whether or not the inhibitory or facilitatory effect was observed in an individual unit seemed to be related to its pattern and its rate of spontaneous activity. Most of the units showing relatively high and regular spontaneous firing were insensitive to the electrical stimulation, and units with a low firing rate and an irregular pattern of activity tended to be affected by the electrical stimulation. The activation of divergent efferent fibers elicited both inhibition and facilitation on the spontaneous afferent activities in all vestibular nerve branchlets, except in the saccular branchlet, where only inhibition was elicited. Electrical stimulation of the central stump of the saccular nerve branchlet, however, could produce both inhibitory and facilitatory effects in other vestibular nerve branchlets.

Observations of the sensing and the tectorial membrane in bullfrog amphibian papilla: their possible functional roles.

Three dimensional reconstructions of the amphibian papilla were performed with light microscopic observations, mainly for the sensing membrane (SM). In horizontal sections of the papilla, the anteromedial end of the SM, which makes contact with the massive anterior portion of the tectorial membrane (TM), is several times thicker than the posterolateral end close to the column of the innervating nerves. This gradient of thickness is observed in all the sections from the dorsal portion attached to the TM to the ventral floor of the papilla. The SM connects to the TM in a topological manner; the anteromedial portion of the TM relates to the anterior end of the SM and the anterolateral and the middle portions of the TM correspond to the sites shifting posteriorly on the SM. The morphology of the SM and its manner of connection to the TM suggest that the SM plays important roles in the occurrence of frequency selectivity and of tonotopic organization of the amphibian papilla.

Somatotopic organization and columnar structure of vibrissae representation in the rat ventrobasal complex.

The region of vibrissae representation in the ventrobasal complex (VB) of the rat was systematically mapped, based on receptive fields of many single neurons. Results showed that the ventralmost row of vibrissae projected to the rostral part of VB, that the dorsal-most row projected to the caudal part, and that the caudalmost vibrissae of each row projected to the most dorsolateral part of VB and more rostral vibrissae to the more ventromedial part. Further, it was revealed that the clusters of neurons receiving projections from any individual vibrissae formed corresponding columns extending from the anterodorsomedial to the posteroventrolateral direction, and that these columns piled up dorsoventrally and anteroposteriorly, with ventral ones shifted progressively medially. When cross sections of these columns were viewed on an oblique horizontal section of VB, a group of columns corresponding to each row lined up from the dorsolateral to the ventromedial direction with a rostral convexity, which means that the third or fourth vibrissa in each row projected most rostrally in that row. These results confirmed previous physiological mapping studies of vibrissal representation and are in good agreement with anatomical studies on barreloid structure in VB.

[A case of von Hippel-Lindau disease showing only spinal cord symptoms].

A rare case of von Hippel-Lindau disease showing only spinal cord symptoms is reported. This 18-year-old boy was admitted to our clinic because of urinary disturbance, slowly progressive muscle weakness and sensory disturbance of his body and four extremities. Myelography demonstrated an expanding spinal cord and a figure of complete block of contrast medium at the lower cervical level. Dilated syrinx below the level of Th-3 was shown by delayed scan (19 hr.) of metrizamide CT myelography. These findings suggest that metrizamide could pass through the cord substance from the subarachnoid space into a syrinx cavity. Contrast enhancement CT scan revealed a slightly high density mass lesion at the level of Th-1 and a more marked tumor stain at the level of C-5 and 6. Syringo-subarachnoid shunt was done but the spinal intramedullary tumors were so deeply situated in the spinal cord that total removal of them was abandoned. The pathological diagnosis was hemangioblastoma. There were also a hemangioma at the right retina and multiple small tumor stains in the cerebellum, but they presented no clinical symptoms.

Analysis of hyperpolarizations induced by glutamate and acetylcholine on Onchidium neurones.

1. Four giant neurones, designated G-H cells, in the right pleural ganglion of the marine pulmonate mollusc, Onchidium verruculatum, showed characteristic membrane hyperpolarization during applications of either acetylcholine (ACh) or L-glutamate. In the presence of ACh the membrane was hyperpolarized only transiently, while in the presence of glutamate the response was maintained. Significant increases in membrane conductance accompanied the changes in membrane potential.2. In excess potassium sea water, a slight hyperpolarization occurred when the normal concentration was increased between one- and twofold. However, depolarization usually occurred when the concentration was increased tenfold except on a few occasions when a slight but definite hyperpolarization occurred. These changes were all accompanied by a substantial increase in the membrane conductance. This hyperpolarization was in all probability the result of an increase in chloride ion permeability caused by the release of an ACh-like transmitter from depolarized presynaptic nerve terminals.3. The reversal levels for glutamate- and ACh-induced hyperpolarization respectively were approximately - 20 and - 17 mV with respect to the resting membrane potential.4. By changing the external ion composition, glutamate- and ACh-induced hyperpolarization were shown to be the result of an increased permeability of the subsynaptic membrane to potassium and chloride ions respectively. It appears therefore that inhibition in the same G-H cells can be activated by two different transmitter substances and that each of them activates a change in the membrane permeability to a different ion.5. The relationship between the concentration of glutamate and the membrane conductance change was suggestive of two glutamate molecules reacting with a single receptor site.