The Angiogenesis Inhibitor Isthmin-1 (ISM1) Is Overexpressed in Experimental Models of Glomerulopathy and Impairs the Viability of Podocytes.

Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease and remains without specific treatment. To identify new events during FSGS progression, we used an experimental model of FSGS associated with nephroangiosclerosis in rats injected with L-NAME (Nω-nitro-L-arginine methyl ester). After transcriptomic analysis we focused our study on the role of Isthmin-1 (ISM1, an anti-angiogenic protein involved in endothelial cell apoptosis. We studied the renal expression of ISM1 in L-NAME rats and other models of proteinuria, particularly at the glomerular level. In the L-NAME model, withdrawal of the stimulus partially restored basal ISM1 levels, along with an improvement in renal function. In other four animal models of proteinuria, ISM1 was overexpressed and localized in podocytes while the renal function was degraded. Together these facts suggest that the glomerular expression of ISM1 correlates directly with the progression-recovery of the disease. Further in vitro experiments demonstrated that ISM1 co-localized with its receptors GRP78 and integrin αvß5 on podocytes. Treatment of human podocytes with low doses of recombinant ISM1 decreased cell viability and induced caspase activation. Stronger ISM1 stimuli in podocytes dropped mitochondrial membrane potential and induced nuclear translocation of apoptosis-inducing factor (AIF). Our results suggest that ISM1 participates in the progression of glomerular diseases and promotes podocyte apoptosis in two different complementary ways: one caspase-dependent and one caspase-independent associated with mitochondrial destabilization.

Roles of tetraspanins during trophoblast development: bioinformatics and new perspectives.

Tetraspanins are a superfamily of membrane proteins found in all eukaryotic organisms. They act as scaffold molecules that regulate the traffic and function of other membrane/signaling proteins, resulting in important downstream cellular consequences. The aim of this work was to use transcriptomes and bioinformatics analysis to identify the tetraspanins (and their partners) involved in trophoblast differentiation. We built a protein-protein interaction network around tetraspanins which revealed that tetraspanins CD9, CD81, and CD82 show a specific expression during trophoblast differentiation. These proteins appeared to be interconnected and to recruit several membrane partners which include integrins, immune-related molecules, and a variety of receptors. During weeks 8 to 24, a CD9 expression trajectory was identified in extravillous trophoblasts, and a website was developed: ( https://extravillous.shinyapps.io/CD9humanEVT/ ). In conclusion, CD81 may, together with CD9 and CD82, be interconnected in controlling trophoblast invasion in the endometrium. CD9 expression trajectory in extravillous trophoblast between weeks 8 and 24 shows the involvement of CD9 in cell adhesion and migration.

Idiopathic nephrotic syndrome and serum permeability factors: a molecular jigsaw puzzle.

Nephrotic syndrome is traditionally defined using the triad of edema, hypoalbuminemia, and proteinuria, but this syndrome is very heterogeneous and difficult to clarify. Its idiopathic form (INS) is probably the most harmful and essentially comprises two entities: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). We will consider some hypotheses regarding the mechanisms underlying INS: (i) the presence of several glomerular permeability factors in the sera of patients that alter the morphology and function of podocytes leading to proteinuria, (ii) the putative role of immune cells. Thanks to recent data, our understanding of these disorders is evolving towards a more multifactorial origin. In this context, circulating factors may be associated according to sequential kinetic mechanisms or micro-environmental changes that need to be determined. In addition, the resulting proteinuria may trigger more proteinuria enhancing the glomerular destabilization.

Comparison of the AN69ST Membrane versus Citrate-Enriched Dialysate on Clotting Events during Hemodialysis without Systemic Anticoagulation.

BACKGROUND: The optimal management of anticoagulation in hemodialyzed patients with a high risk of bleeding is controversial. METHODS: We compared premature termination of dialysis caused by clotting events between AN69ST membranes (G1) and 0.8 mmol/L citrate-enriched dialysate (G2). The number of sessions that had increased venous pressure (VP) and variations in urea-reduction ratio (URR) were analyzed. RESULTS: Six hundred and two sessions were analyzed in 259 patients: 22.4% had sessions that ended prematurely (25% in G1 and 19.1% in G2, p = ns, OR 0.60 [0.34-1.08], p = 0.08). The increase in VP was lower in G2 (23 vs. 70, p < 0.001). URR was higher in G2 (0.56 vs. 0.60, p < 0.001). CONCLUSION: Clotting events that led to the termination of dialysis were comparable in the 2 groups. However, UUR was better in G2, and the number of patients with increased VP in the sessions was lower in G2. SHORT SUMMARY: Our study compared the effects of the AN69ST membrane and citrate-enriched dialysate on clotting events during the dialysis of 259 patients with a high risk of bleeding. URR was significantly better and fewer cases of increased VP occurred in the citrate group compared to the AN69 ST group. No significant difference was observed regarding the need to prematurely terminate a dialysis session.

Protein A immunoadsorption cannot significantly remove the soluble receptor of urokinase from sera of patients with recurrent focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a serious disease, the pathogenesis of which is unknown. Its recurrence after transplantation (Tx) and its partial remission after treatment with immunoadsorption (IA) on a protein A column indicate the existence of a circulating factor responsible for the disease that is able to bind to a protein A column. Recently, the soluble receptor of urokinase (suPAR) was described as the factor responsible for FSGS. We tested the capacity of suPAR to bind to protein A and to be eliminated by IA. METHODS: We measured suPAR in eluates of protein A columns from seven patients with recurrent FSGS after Tx (rFSGS) treated with IA, and in the serum of 13 patients with rFSGS and 11 healthy donors (HDs). Additionally, the plasma of these patients was immunoadsorbed in vitro on a protein A Sepharose column, and we quantified suPAR in the eluates and in pre- and post-column samples. RESULTS: The concentration of suPAR was higher in the plasma of patients with rFSGS than that of HD patients. However, the concentration of suPAR was similar before and after IA on protein A for the rFSGS and HD samples. The suPAR concentration was very low in the eluates from protein A columns incubated with plasma from HD or rFSGS patients. However, 85% of rFSGS patients showed a decrease in immunoglobulin G and proteinuria. CONCLUSIONS: Thus, suPAR does not significantly bind to protein A in vitro or in vivo.

Efficacy and safety of the H1N1 monovalent vaccine in renal-transplant recipients and dialysis patients.

BACKGROUND: The (H1N)1v influenza virus infection emerged in 2009 as a serious disease in targeted populations. Herein, we report on the tolerability and efficacy of (anti-H1N1)v vaccination in dialysis and transplant patients. METHODS: 18 renal-transplant recipients (RTR) and 19 dialysis patients (DP) [12 patients treated with peritoneal dialysis (PDP), 7 patients treated with haemodialysis (HDP)] were enrolled. DPs received one monovalent H1N1 adjuvanted-vaccine injection, and RTRs received two unadjuvanted vaccine injections within a 21-day period. Serologic response was defined as a haemagglutination inhibition titre of > 40 (seroprotection) and/or at least a four-fold increase in antibody titre from baseline (seroconversion). RESULTS: Seroprotection rate after vaccination was greater in DPs than RTRs (p = 0.007), as was seroconversion (p = 0.001). Serologic response was similar in PDPs and HDPs. CONCLUSIONS: Serologic response was satisfactory in DPs, whichever dialysis mode (DPD or HDP). It was low in RTRs as compared to DPs.

[Idiopathic nephrotic syndrome: une Arlésienne?] / Syndrome néphrotique idiopathique et facteurs circulants - Une Arlésienne ?

The renal filtration is ensured by the kidney glomeruli selective for filtering the blood. The main actor of the glomerular filter is the podocyte whose interlaced pedicels bear protein complexes (nephrin, podocin, etc.) creating a molecular sieve (slit diaphragm) to achieve the filtration. Alterations of these podocytes lead to massive proteinuria, which characterizes the nephrotic syndrome. The idiopathic form is one of the most malignant and essentially comprises two entities: minimal change disease and focal segmental glomerulosclerosis. Many observations indicated that (1) immune cells are involved and that (2) there are several permeability factors in the blood that affect the morphology and function of podocytes (slit diaphragm with fractional foot processes fusion/effacement). Evidence for a permeability factor was chiefly derived from remission of proteinuria observed after implantation of a kidney with FSGS in healthy recipients or with other kidney diseases. Today, we are moving towards a multifactorial conception of the nephrotic syndrome where all these barely known factors could be associated according to a sequential kinetic mechanism that needs to be determined.

TITLE: Syndrome néphrotique idiopathique et facteurs circulants - Une Arlésienne ? ABSTRACT: La fonction d'excrétion du rein fait intervenir des glomérules chargés de filtrer sélectivement le sang. L'acteur principal du filtre glomérulaire est le podocyte dont les pédicelles entrelacés portent des complexes moléculaires (néphrine, podocine, etc.) qui sont responsables du fonctionnement de la barrière de filtration (diaphragme de fente). Des altérations de ces podocytes entraînent une protéinurie massive qui caractérise le syndrome néphrotique. Parmi les formes les plus malignes de cette pathologie, se trouve le syndrome néphrotique idiopathique dont la physiopathologie reste inconnue. Ce syndrome regroupe essentiellement deux entités : les lésions glomérulaires minimes et la hyalinose segmentaire et focale. Ces pathologies impliqueraient les cellules du système immunitaire et plusieurs facteurs de perméabilité circulants qui agiraient sur la morphologie et le fonctionnement des podocytes.

Optimal management of primary focal segmental glomerulosclerosis in adults.

Focal segmental glomerulosclerosis (FSGS) is a frequent glomerular kidney disease that is revealed by proteinuria or even nephrotic syndrome. A diagnosis can be established from a kidney biopsy that shows focal and segmental glomerulosclerosis. This histopathological lesion may be caused by a primary podocyte injury (idiopathic FSGS) but is also associated with other pathologies (secondary FSGS). The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure. In addition, in some cases, FSGS can recur on a graft after kidney transplantation: an unidentified circulating factor may be implicated. Understanding of its physiopathology is unclear, and it remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics. This study reviews the treatment of primary FSGS and the recurrence of FSGS after kidney transplantation in adults.

Caspase-8 sumoylation is associated with nuclear localization.

The cysteine protease caspase-8 plays a pivotal role in the initiation of different apoptotic pathways and controls the maturation and differentiation of various cell types including neurons, fibroblasts and lymphocytes. Specific substrates of caspase-8 are present in both the cytoplasm and the nucleus, which may determine the ultimate biological effect of caspase-8. However, the mechanisms regulating the cellular localization of caspase-8 are still unknown. We show here that, in contrast to other caspases such as caspase-9 and -3, caspase-8 can be sumoylated at lysine 156. This sumoylation (i) is associated with the nuclear localization of caspase-8 and (ii) did not impair caspase-8 activation.

Bmcc1s interacts with the phosphate-activated glutaminase in the brain.

Bmcc1s, a brain-enriched short isoform of the BCH-domain containing molecule Bmcc1, has recently been shown to interact with the microtubule-associated protein MAP6 and to regulate cell morphology. Here we identified kidney-type glutaminase (KGA), the mitochondrial enzyme responsible for the conversion of glutamine to glutamate in neurons, as a novel partner of Bmcc1s. Co-immunoprecipitation experiments confirmed that Bmcc1s and KGA form a physiological complex in the brain, whereas binding and modeling studies showed that they interact with each other. Overexpression of Bmcc1s in mouse primary cortical neurons impaired proper mitochondrial targeting of KGA leading to its accumulation within the cytoplasm. Thus, Bmcc1s may control the trafficking of KGA to the mitochondria.