Stage lighting on PAR-1: a step further in the understanding of acquired focal and segmental glomerulosclerosis

The pathogenic mechanisms of acquired focal and segmental glomerulosclerosis are only partially known and represent a medical challenge in nephrology. The article by May et al. sheds additional light on previous data indicating the key role of the protease activated receptor 1. The new evidence is based on in vivo studies in relevant animal models and on patient biopsies and represents a significant step forward in the understanding of this pathological condition

The Enigmatic Emerging Role of the C-Maf Inducing Protein in Cancer

International audienceThe C-Maf-Inducing protein (CMIP) was first described as overexpressed in T cell subpopulations of idiopathic nephrotic syndrome (INS) patients. Later, it was found concomitantly upregulated in podocytes. CMIP expression has also been reported in several types of cancer, including blood malignancies and solid tumors, in many cases accompanied by nephrotic syndrome. In addition to these observations, the duality of CMIP overexpression in the kidney and INS lesions, has been extensively reported as one of the adverse effects of anticancer therapy based on anti-receptor tyrosine kinase drugs. As a consequence, a growing body of evidence points at CMIP as playing a role in cancer. This includes its reciprocal regulatory ties with NF-κB and WT1, and the more recent reports showing an involvement in regulatory circuits in cancer cells. The ensemble of the current information justifies to propose CMIP as an important piece of the puzzle of biological systems involved in cancer and other diseases and its potential as a target

Mécanismes moléculaires du syndrome néphrotique idiopathique acquis

Résumé de la thèse:Le syndrome néphrotique idiopathique (SNI) est la forme la plus fréquente de néphropathies glomérulaires et résulte d'altérations touchant les podocytes. La progression de la maladie est associée à une déplétion podocytaire et l'apparition de glomérulosclérose. Malgré de nombreuses études moléculaires et des avancées scientifiques indiscutables sur les formes génétiques, la pathogénie du SNI reste une énigme.Nous avons trouvé que la protéine c-mip est spécifiquement induite dans les podocytes des patients atteints de SNI.Nous avons montré que les souris transgéniques c-mip développent une protéinurie néphrotique qui n'est associée ni à des lésions inflammatoires glomérulaires ou interstitielles, ni à des dépôts de complexes immuns circulants ou de complément. Les études in vitro et in vivo ont démontré que c-mip se lie à Fyn et bloque la liaison de Fyn avec la néphrine et N WASP. Il en résulte une inhibition de la voie de signalisation de la néphrine et l'incapacité de N-WASP à recruter Nck, ce qui altère l'organisation du cytosquelette podocytaire et contribue au développement de la protéinurie masssive.D'autre part, nous avons montré que Wt1 se lie au promoteur de c-mip et bloque sa transactivation. Au cours du SNI acquis, les résultats obtenus in vitro et dans les souris transgéniques suggèrent que c-mip inhibe la transcription du gène de Wt1 médiée par NF- B, interagit avec Wt1 via son domaine LRR et favorise la dégradation de Wt1 par le protéasome.Nous avons également trouvé que c-mip interfère avec l'activation de la voie NF- B en destabilisant la sous-unité RelA, tandis que la sous-unité p50 est préservée. Les résultats in vitro et dans le modèle murin suggèrent que c-mip est dotée de propriétés pro-apoptotiques.Ces travaux montrent que la protéine c-mip joue un rôle crucial dans la physiopathologie du SNI et constitue une cible thérapeutique de choix.SummaryPodocyte damages are the initiating event in the pathogenesis of idiopathic nephrotic syndrome (INS). Progression of podocyte disease is associated with cellular depletion and appearance of glomerulosclerosis. The molecular pathophysiology of this disease remains an enigma.We showed that c-mip (c-maf inducing protein) is up-regulated in podocytes during the active phase of INS.We generated c-mip transgenic mice overexpressing c-mip specifically in podocytes. These mice developed morphological and biochemical alterations similar to INS. We demonstrated that c-mip switches off podocyte proximal signaling by preventing the interaction between Fyn and nephrin, resulting in the inhibition of nephrin phosphorylation in vitro and in vivo. Moreover, we found that the in vivo interactions of Fyn with Nck and N WASP are inhibited, which may account for disorganization of the cytoskeleton and the effacement of foot processes.We showed that, under physiological conditions, Wt1 inhibits the transcriptional induction of c-mip. Conversely, we demonstrated that, under pathological conditions, c-mip inhibits NF B mediated-Wt-1 transcription, interacts in vitro and in vivo with Wt1 via its LRR domain, and targets Wt1 to proteasome degradation.We also observed that the induction of c-mip in patients with INS is correlated with a downregulation of RelA in podocytes. We showed that c-mip alters NF- B signaling by destabilizing the RelA protein, while p50 is preserved. Morever, the results established in stably transfected podocytes and in transgenic mice suggest that c-mip is a proapoptotic protein.Collectively, these data postulate that c-mip functions as a negative regulator and plays a central role in podocytes disorders during INS.PARIS-EST-Université (770839901) / SudocPARIS12-Bib. électronique (940280011) / SudocSudocFranceF

Pathogénie du syndrome néphrotique à lesions glomérulaires minimes

Le syndrome néphrotique idiopathique (SNI) est une néphropathie glomérulaire définie par une protéinurie massive associée à une hypoalbuminémie, sans lésions inflammatoires rénales ni dépôts de complexes immuns circulants. Le SNI à lésions glomérulaires minimes (SNLGM) représente la forme la plus fréquente des syndromes néphrotiques et se caractérise par des perturbations du système immunitaire et une atteinte rénale podocytaire dont le mécanisme reste obscur. La phase active de la maladie est associée à une augmentation du nombre de lymphocytes T et B et à une production accrue de cytokines. Les principales perturbations lymphocytaires qui semblent caractéristiques du SNLGM sont l’inhibition de l’hypersensibilité de type retardé, les anomalies de la commutation isotypique et une polarisation lymphocytaire T qui ne correspond ni à une voie de type Th1 ou Th2 classique et qui résulte d’une activation transcriptionnelle anormale. Le lien moléculaire entre l’atteinte immunologique et l’atteinte podocytaire reste non élucidé

9-O Acetylated Gangliosides in Health and Disease

Glycosphingolipids comprise a lipid class characterized by the presence of sugar moieties attached to a ceramide backbone. The role of glycosphingolipids in pathophysiology has gained relevance in recent years in parallel with the development of analytical technologies. Within this vast family of molecules, gangliosides modified by acetylation represent a minority. Described for the first time in the 1980s, their relation to pathologies has resulted in increased interest in their function in normal and diseased cells. This review presents the state of the art on 9-O acetylated gangliosides and their link to cellular disorders

Gangliosides in podocyte biology and disease

International audienceGangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis-ganglioside synthases-and their degradation-glycosidases-. Dysregulation of their abundance results in rare and common diseases. In this review we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites

Electroluminescence and space charge in nanodielectrics subjected to AC voltage

NRC publication: Ye

Pharmacology of Tyrosine Kinase Inhibitors: Implications for Patients with Kidney Diseases

International audienceTyrosine kinase inhibitors (TKI) have introduced a significant advancement in cancer management. These compounds are administered orally, and their absorption holds a pivotal role in determining their variable efficacy. They exhibit extensive distribution within the body, binding strongly to both plasma and tissue proteins. Often reliant on efflux and influx transporters, TKI undergo primary metabolism by intestinal and hepatic cytochrome P450 enzymes, with non-kidney clearance being predominant. Due to their limited therapeutic window, many TKI display considerable intra- and interindividual variability. This review offers a comprehensive analysis of the clinical pharmacokinetics of TKI, detailing their interactions with drug transporters and metabolic enzymes, while discussing potential clinical implications. The prevalence of kidney conditions, such as acute kidney injury (AKI) and chronic kidney disease (CKD), among cancer patients is explored in terms of their impact on TKI pharmacokinetics. Lastly, the potential nephrotoxicity associated with TKI is also examined.</jats:p

Nephrotoxicity of Anti-Angiogenic Therapies

International audienceThe use of inhibitors of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling for the treatment of cancer has increased over the last decade. This signaling pathway plays a fundamental role in angiogenesis and also in kidney physiology. The emergence of anti-angiogenic therapies has led to adverse nephrotoxic effects, despite improving the outcomes of patients. In this review, we will present the different anti-angiogenic therapies targeting the VEGFR pathway in association with the incidence of renal manifestations during their use. In addition, we will discuss, in detail, the pathophysiological mechanisms of frequent renal diseases such as hypertension, proteinuria, renal dysfunction, and electrolyte disorders. Finally, we will outline the cellular damage described following these therapies