Laurent Mesnard

Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN

Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN.

Delayed angioplasty after renal thrombosis

When renal arterial thrombosis occurs, the etiologic process plays an important role in the impact of ischemia on renal tissue. If the occlusion is caused by trauma, infarction rapidly occurs. However, when renal arterial thrombosis results from other processes, collateral vessels may develop and thus enables a prolonged ischemia without necrosis. The following is a case report of an acute renal failure caused by renal arterial thrombosis of a single functional kidney, which had a favorable outcome despite delayed treatment by percutaneous angioplasty. This report suggests that detection by ultrasonography of a venous renal flow could be of significant value to assess a collateral vascularization and thus should require an arteriography with angioplasty even after a delayed presentation.

The Case ∣ The smoker and the nephrologist

A 28-year-old man, a native of Morocco, was hospitalized for acute renal failure associated with persistent vomiting. The patient first presented at age 16 with cyclical episodes of abdominal pain with vomiting, relieved transiently by compulsive hot baths. He had continuously smoked 15 cigarettes and 5 cannabis ‘joints’ a day since the age of 14 years. He denied consumption of medication and other illicit drugs or alcohol.

Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.Crescentic rapidly progressive glomerulonephritis is a severe form of glomerula disease characterized by podocyte proliferation and migration. Here Henique et al. demonstrate that inhibition of miRNA-92a prevents kidney failure by promoting the expression of CDK inhibitor p57Kip2 that regulates podocyte cell cycle.

Adaptive Somatic Mutations Calls with Deep Learning and Semi-Simulated Data

A number of approaches have been developed to call somatic variation in high-throughput sequencing data. Here, we present an adaptive approach to calling somatic variations. Our approach trains a deep feed-forward neural network with semi-simulated data. Semi-simulated datasets are constructed by planting somatic mutations in real datasets where no mutations are expected. Using semi-simulated data makes it possible to train the models with millions of training examples, a usual requirement for successfully training deep learning models. We initially focus on calling variations in RNA-Seq data. We derive semi-simulated datasets from real RNA-Seq data, which offer a good representation of the data the models will be applied to. We test the models on independent semi-simulated data as well as pure simulations. On independent semi-simulated data, models achieve an AUC of 0.973. When tested on semi-simulated exome DNA datasets, we find that the models trained on RNA-Seq data remain predictive (sens 0.4 & spec 0.9 at cutoff of P > = 0.9), albeit with lower overall performance (AUC=0.737). Interestingly, while the models generalize across assay, training on RNA-Seq data lowers the confidence for a group of mutations. Haloplex exome specific training was also performed, demonstrating that the approach can produce probabilistic models tuned for specific assays and protocols. We found that the method adapts to the characteristics of experimental protocol. We further illustrate these points by training a model for a trio somatic experimental design when germline DNA of both parents is available in addition to data about the individual. These models are distributed with Goby (http://goby.campagnelab.org).