Podocyte Glutamatergic Signaling Contributes to the Function of the Glomerular Filtration Barrier

Podocytes possess the complete machinery for glutamatergic signaling, raising the possibility that neuron-like signaling contributes to glomerular function. To test this, we studied mice and cells lacking Rab3A, a small GTPase that regulates glutamate exocytosis. In addition, we blocked the glutamate ionotropic N-methyl-d-aspartate receptor (NMDAR) with specific antagonists. In mice, the absence of Rab3A and blockade of NMDAR both associated with an increased urinary albumin/creatinine ratio. In humans, NMDAR blockade, obtained by addition of ketamine to general anesthesia, also had an albuminuric effect. In vitro, Rab3A-null podocytes displayed a dysregulated release of glutamate with higher rates of spontaneous exocytosis, explained by a reduction in Rab3A effectors resulting in freedom of vesicles from the actin cytoskeleton. In addition, NMDAR antagonism led to profound cytoskeletal remodeling and redistribution of nephrin in cultured podocytes; the addition of the agonist NMDA reversed these changes. In summary, these results suggest that glutamatergic signaling driven by podocytes contributes to the integrity of the glomerular filtration barrier and that derangements in this signaling may lead to proteinuric renal diseases.It is widely recognized that most glomerular diseases are characterized by defects of the filtration barrier, where podocytes play a central role. Mutations of single podocyte proteins have been found at the basis of human nephrotic syndromes,¹ and podocyte deletion of the same molecules causes heavy proteinuria in experimental models.^2–8Podocytes are highly ramified cells: From the cell body depart a number of primary processes, further originating secondary foot processes. Starting from these features, it has been demonstrated that podocytes share numerous similarities with neurons: They both are terminally differentiated cells, have a common cytoskeletal organization, and have a common machinery of process formation.⁹ Furthermore, a number of expression-restricted proteins, such as nephrin,² Neph1 and Neph2,¹⁰ GLEPP1,¹¹ CAT3 and EAAT2,¹² synaptopodin,¹³ drebrin,¹⁴ and Sam68-like-MP2,¹⁵ specifically belong to the podocyte and the neuron.Our group has contributed to this line of research, initially by describing in podocytes the presence of Rab3A, a small GTPase that is mostly enriched in synaptic vesicles because it tightly modulates highly regulated exocytosis by acting through a number of effector molecules, including rabphilin-3a and Synapsin-I.¹⁶ After finding that in podocytes, as it occurs in neurons, Rab3A associates to glutamate-containing vesicles along cell processes, we discovered that podocytes are equipped with a complete neuron-like glutamatergic signaling system.¹⁷ We described that podocytes possess functional synaptic-like microvesicles and renal glomeruli express cognate glutamate transporters and receptors. These properties strengthened the analogies between podocytes and neurons and offered a rational interpretation to the biochemical similarity of foot process and synaptic adhesion complexes¹⁷; however, the role played by glutamate signaling in podocytes remained unanswered, and nothing was known about its relevance to podocyte and glomerular homeostasis. To get more details on the requirement of this neuron-like system of signaling by podocytes, we first conducted a preliminary analysis on its temporal appearance during podocyte differentiation. Then we studied conditions in which it was altered, on the vesicle and on the receptor side. The vesicular component was analyzed by studying the consequences of the absence of Rab3A. On the receptor side, we antagonized the ionotropic N-methyl-d-aspartate receptor (NMDAR), that we found present in human and rodent glomeruli, as well as in podocyte cell cultures.¹⁷ Both Rab3A and NMDAR1 glomerular synthesis were also confirmed by in situ hybridization (Supplemental Figure 1) and by microarray expression data.¹⁷     

The Second Procedure Combining Complete Cytoreductive Surgery and Intraperitoneal Chemotherapy for Isolated Peritoneal Recurrence: Postoperative Course and Long-Term Outcome

Background  

Complete cytoreductive surgery (CCRS) with intraperitoneal chemotherapy (IPC) is becoming the gold-standard treatment for resectable peritoneal carcinomatosis, when feasible. However, this approach has not yet been evaluated for isolated peritoneal re-recurrences after previous IPC. The aim of this study was to evaluate the postoperative course and long-term outcome after repeat (re-)CCRS + IPC.     

Patients on dialysis and the psychological aging process

In reference to psychopathology, the authors highlight several indicators of the aging dialysed patient's psychological functioning. The aim of this work is to extract some indicators in order to help these patients to experience a pleasant aging, in spite of a difficult disease state, constraining care and the presence of several side effects.     

Panel review of anaplastic oligodendroglioma from European Organization For Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome

The diagnosis of anaplastic oligodendroglioma (AOD) or anaplastic oligoastrocytoma (AOA) is subject to interobserver variation. The aim of this study was to estimate consensus in typing and grading of these tumors using tumor material collected in a large prospective randomized phase III study and to correlate the consensus diagnosis with the 1p/19q status of the tumors and the clinical outcome. The available pathology material of the first 150 patients, randomized into the European Organization for Research and Treatment of Cancer Trial 26951, was reviewed by an independent panel of 9 neuropathologists. The presence of deletions of 1p and 19q was assessed by fluorescence in situ hybridization with locus-specific probes. The panel reached consensus on the diagnosis of AOD in 52% of the tumors that had been diagnosed as AOD by the local pathologists, whereas only 8% of the local diagnosis of AOA was confirmed with consensus. The concordance on the panel diagnosis of AOD was high (intraclass correlation = 86%). The survival curves for AOD with 1p/19q loss, AOD without these losses, and AOA without 1p/19q loss ran separately in this order. The absence of necrosis and the presence of endothelial abnormalities were correlated with better outcomes. In multivariate analysis, patients' age, 1p/19q loss, and necrosis were identified as independent prognostic factors.     

Modulation of morphine and alcohol motor stimulant effects by cannabinoid receptors ligands

Previous studies evidenced in rats the suppression by cannabinoids of motor stimulant effects of various drugs of abuse. Here we investigated, in mice, the effects of an acute or a chronic administration with the cannabinoid agonist HU 210 on the motor stimulant effects of either morphine or alcohol. HU 210 (12.5-200 microg/kg), when acutely administered, antagonized the stimulant effects of morphine (7.5 mg/kg) or alcohol (1 or 1.5 g/kg). A tolerance to this antagonistic interaction with morphine and alcohol occurred after a 7-day or a 14-day HU 210 treatment, leading to the reappearance of morphine- and alcohol-induced stimulation. The CB1 receptor antagonist rimonabant (10 mg/kg) enhanced the stimulant effect induced by low doses of morphine (5 or 7.5 mg/kg). Rimonabant (3 or 10 mg/kg) altered the locomotor effect of alcohol in a biphasic manner. It enhanced the stimulant effect of low doses of alcohol (1 or 1.5 g/kg) while decreasing the locomotor activity of mice treated with a high dose (3 g/kg) of alcohol. Furthermore, rimonabant (3 and 10 mg/kg) enhanced the duration of alcohol-induced loss of righting reflex (4 g/kg), suggesting a dual implication of cannabinoidergic pathways in acute effects of alcohol.