Whole-genome sequencing revealed a novel structural variant in causing autosomal dominant Alport syndrome: A case report.

Next-generation sequencing has substantially transformed the genomic diagnosis of individuals affected by inherited renal disorders. Indeed, accurate and rapid diagnostic for patients with suspected genetic kidney diseases is not only important for prognosis and patient management but also for family counseling. Alport syndrome, a genetic disease primarily affecting the basement membrane, is characterized by hematuria, progressive kidney failure, hearing impairment, as well as ocular abnormalities and stems from mutations in genes encoding type IV collagen.

MUC1 Drives the Progression and Chemoresistance of Clear Cell Renal Carcinomas.

While the transmembrane glycoprotein mucin 1 (MUC1) is clustered at the apical borders of normal epithelial cells, with transformation and loss of polarity, MUC1 is found at high levels in the cytosol and is uniformly distributed over the entire surface of carcinoma cells, where it can promote tumor progression and adversely affects the response to therapy. Clear cell renal cell carcinoma (ccRCC), the main histotype of kidney cancer, is typically highly resistant to conventional and targeted therapies for reasons that remain largely unknown. In this context, we investigated whether MUC1 also plays a pivotal role in the cellular and molecular events driving ccRCC progression and chemoresistance.

Integrating rare genetic variants into DPYD pharmacogenetic testing may help preventing fluoropyrimidine-induced toxicity.

Variability in genes involved in drug pharmacokinetics or drug response can be responsible for suboptimal treatment efficacy or predispose to adverse drug reactions. In addition to common genetic variations, large-scale sequencing studies have uncovered multiple rare genetic variants predicted to cause functional alterations in genes encoding proteins implicated in drug metabolism, transport and response. To understand the functional importance of rare genetic variants in DPYD, a pharmacogene whose alterations can cause severe toxicity in patients exposed to fluoropyrimidine-based regimens, massively parallel sequencing of the exonic regions and flanking splice junctions of the DPYD gene was performed in a series of nearly 3000 patients categorized according to pre-emptive DPD enzyme activity using the dihydrouracil/uracil ([UH]/[U]) plasma ratio as a surrogate marker of DPD activity.

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects.

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity.

The Versatile Role of miR-21 in Renal Homeostasis and Diseases.

MicroRNAs (miRNAs) are small, non-coding RNA species that control gene expression and confer robustness to biological processes. Over the last two decades, their important roles during kidney development, homeostasis and the treatment of diseases have been established, in particular during the onset and progression of various forms of acute and chronic renal disorders. In recent years, miR-21, one of the best-characterized miRNAs to date, has received much attention in renal physiology in particular given its high degree of conservation and expression in kidneys, as well as its potent pathogenic role in various debilitating renal diseases.

MUC1 Mitigates Renal Injury and Inflammation in Endotoxin-Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-inflammatory Macrophages Infiltration.

Sepsis is the leading cause of acute kidney injury (AKI) in critical care patients. A cornerstone of sepsis-associated AKI is dysregulated inflammation driven by excessive activation of Toll-like receptor 4 (TLR4) pathway. MUC1, a membrane-bound mucin expressed in both epithelial tubular cells and renal macrophages, has been shown to be involved in the regulation of TLRs.

[Fundamental aspects of oncogenesis].

Tumorigenesis has traditionally been considered as a multi-step process involving the activation of oncogenes as well as the inactivation of tumor suppressor genes. However, the mechanisms driving cancer initiation and progression are not restricted to molecular alterations and instead should be viewed as a complex process that interfaces with the entire organism. This didactic review provides an integrated and global view of the key fundamental principles of cancer development.

Tubulointerstitial damage and interstitial immune cell phenotypes are useful predictors for renal survival and relapse in antineutrophil cytoplasmic antibody-associated vasculitis.

The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review.

Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation.

Although Tacrolimus is an immunosuppressive drug widely used in renal transplantation, its chronic use paradoxically induces nephrotoxic effects, in particular renal fibrosis, which is responsible for chronic allograft dysfunction and represents a major prognostic factor of allograft survival. As molecular pathways and mechanisms involved in Tacrolimus-induced fibrogenic response are poorly elucidated, we assessed whether miRNAs are involved in the nephrotoxic effects mediated by Tacrolimus. Treatment of CD-1 mice with Tacrolimus (1 mg/kg/d for 28 days) resulted in kidney injury and was associated with alteration of a gene expression signature associated with cellular stress, fibrosis and inflammation.

Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.

Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer.

Dual role of MUC1 mucin in kidney ischemia-reperfusion injury: Nephroprotector in early phase, but pro-fibrotic in late phase.

Acute kidney injury (AKI) is characterized by acute tubular necrosis (ATN) which involves mainly proximal tubules. Past AKI is associated with higher risk of chronic kidney disease (CKD). The MUC1 mucin is a large glycoprotein responsible for epithelial protection and locates to convoluted distal tubules and collecting ducts.

Donor caveolin 1 (CAV1) genetic polymorphism influences graft function after renal transplantation.

Background: Identification of the culprit genes underlying multifactorial diseases is one of the most important current challenges of molecular genetics. While recent advances in genomics research have accelerated the discovery of susceptibility genes, much remains to be learned about the functions of disease-associated genetic variants. Recently, Moore and co-workers identified, in the donor genome, an association between a common genetic variant (rs4730751) in the gene encoding caveolin-1 (CAV1), a major structural component of caveolae, and long-term allograft survival.

Donor ABCB1 genetic polymorphisms influence epithelial-to-mesenchyme transition in tacrolimus-treated kidney recipients.

Aim: The contribution of epithelial-mesenchymal transition (EMT) has been suggested in renal transplant recipients receiving calcineurin inhibitors and developing nephrotoxicity.

Materials & Methods: We assessed whether interindividual variability in tacrolimus pharmacokinetics is associated with the occurrence in tubular cells of two EMT markers (vimentin, β-catenin) detected at 3-month in 140 allograft biopsies. We investigated whether genetic polymorphisms affecting CYP3A5 and ABCB1 influence EMT and kidney fibrosis.

Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models.

Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues.

The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells.

MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux.

Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth.

Loss of secreted phospholipase A2 receptor (PLA2R1) has recently been found to render human primary cells more resistant to senescence whereas increased PLA2R1 expression is able to induce cell cycle arrest, cancer cell death or blockage of cancer cell transformation in vitro, suggesting that PLA2R1 displays tumor suppressive activities. Here we report that PLA2R1 expression strongly decreases in samples of human renal cell carcinoma (RCC). Knockdown of PLA2R1 increases renal cancer cell tumorigenicity supporting a role of PLA2R1 loss to promote in vivo RCC growth.

FibromiRs: translating molecular discoveries into new anti-fibrotic drugs.

Fibrosis, or tissue scarring, is defined as excessive and persistent accumulation of extracellular matrix components in response to chronic tissue injury. Fibrosis is a pathological feature characterizing nearly all forms of chronic organ failure. Fibroproliferative disorders of liver, kidney, heart, and lung are frequently associated with considerable morbidity and mortality worldwide.

MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway.

MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carcinogenetic pathway. In this context, we assessed the effects of MUC1 overexpression on renal cancer cells properties.

MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/β-catenin pathway and interaction with SNAIL promoter.

MUC1 is overexpressed in human carcinomas. The transcription factor SNAIL can activate epithelial-mesenchymal transition (EMT) in cancer cells. In this study, in renal carcinoma, we demonstrate that (i) MUC1 and SNAIL were overexpressed in human sarcomatoid carcinomas, (ii) SNAIL increased indirectly MUC1 expression, (iii) MUC1 overexpression induced EMT, (iv) MUC1 C-terminal domain (MUC1-C) and β-catenin increased SNAIL transcriptional activity by interaction with its promoter and (v) blocking MUC1-C nuclear localization decreased Wnt/β-catenin signaling pathway activation and SNAIL expression.

PLA2R1 mediates tumor suppression by activating JAK2.

Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown.

Isolation and characterization of a primary proximal tubular epithelial cell model from human kidney by CD10/CD13 double labeling.

Renal proximal tubular epithelial cells play a central role in renal physiology and are among the cell types most sensitive to ischemia and xenobiotic nephrotoxicity. In order to investigate the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries, a stable and well-characterized primary culture model of proximal tubular cells is required. An existing model of proximal tubular cells is hampered by the cellular heterogeneity of kidney; a method based on cell sorting for specific markers must therefore be developed.