A central role for Galectin 3 during renal epithelial cell morphogenesis after nephrectomy

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Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach. Nat Med 11

Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-α (TGF-α) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-α or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-α and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases. Regardless of etiology, most human kidney diseases are characterized by an initial injury, followed by progression of renal lesions to complete parenchymal destruction and end-stage renal failure 1 . Clinical and experimental studies have shown that angiotensin II (AngII), the major renin-angiotensin system effector, has an important role in the biological process leading to renal deterioration. Indeed, pharmacological inhibition of the renin-angiotension system attenuates development of renal lesions in several experimental models of renal injury 2 and retards progressive loss of renal function in individuals with chronic kidney disease (CKD) 3 . Conversely, individuals with genetic variants associated with higher renin-angiotensin system activity are at increased risk for progression of chronic renal failure 4 . It has been suggested that AngII causes renal injury through renal hemodynamic effects and stimulation of kidney growth and matrix deposition 5 , but the molecular pathways underlying these phenomena remain largely unidentified. AngII acts on at least two structurally and pharmacologically distinct G-protein-coupled receptors (GPCRs), AT 1 and AT 2 (ref. 6). Renal cells predominantly express AT 1 receptors, which mediate the majority of known AngII actions 7 . AT 1 receptors activate Gq-phospholipase C to generate inositol triphosphate and diacylglycerol, thereby increasing intracellular calcium and stimulating protein kinase C 8 . Additionally, activation of AT 1 receptors promotes tyrosine phosphorylation and stimulates mitogen-activated protein kinases and proliferation 9,10 . How AT 1 receptors, which lack intrinsic tyrosine kinase activity, induce these events is unclear, but recent evidence suggests that 'transactivation' of the epidermal growth factor receptor (EGFR) is involved 11 , and may require several intermediary signaling molecules including Ca 2+ , protein kinase C and cytosolic tyrosine kinases 9 . Recently, it has been shown that metalloprotease-dependent release of EGFR ligands from cells is also involved in GCPR-induced EGFR transactivation 12 . Whether and by which molecular mechanisms AngII transactivates EGFR in renal cells during kidney diseases is unknown. EGFR binds members of a family of growth factors, comprised of EGF, transforming growth factor-α (TGF-α), heparin-binding EGF-like growth factor, amphiregulin, epiregulin, betacellulin and epigen 13 . All family members are synthesized as membrane-anchored precursors that can be processed by specific metalloproteases to release soluble bioactive factors from the cell surface 13 . In the kidney, both EGFR and its ligands are abundantly expressed along the nephron, suggesting a paracrine-autocrine syste

Detect tissue heterogeneity in gene expression data with BioQC

Abstract Background Gene expression data can be compromised by cells originating from other tissues than the target tissue of profiling. Failures in detecting such tissue heterogeneity have profound implications on data interpretation and reproducibility. A computational tool explicitly addressing the issue is warranted. Results We introduce BioQC, a R/Bioconductor software package to detect tissue heterogeneity in gene expression data. To this end BioQC implements a computationally efficient Wilcoxon-Mann-Whitney test and provides more than 150 signatures of tissue-enriched genes derived from large-scale transcriptomics studies. Simulation experiments show that BioQC is both fast and sensitive in detecting tissue heterogeneity. In a case study with whole-organ profiling data, BioQC predicted contamination events that are confirmed by quantitative RT-PCR. Applied to transcriptomics data of the Genotype-Tissue Expression (GTEx) project, BioQC reveals clustering of samples and suggests that some samples likely suffer from tissue heterogeneity. Conclusions Our experience with gene expression data indicates a prevalence of tissue heterogeneity that often goes unnoticed. BioQC addresses the issue by integrating prior knowledge with a scalable algorithm. We propose BioQC as a first-line tool to ensure quality and reproducibility of gene expression data

Correction to: Detect tissue heterogeneity in gene expression data with BioQC

After the publication of this work [1], a mistake was noticed in the Eq. 1. Given an m  ×  n expression matrix with m genes and samples of n tissues, the correct definition of the Gini index for gene i is

Spindle pole cohesion requires glycosylation-mediated localization of NuMA

Glycosylation is critical for the regulation of several cellular processes. One glycosylation pathway, the unusual O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) has been shown to be required for proper mitosis, likely through a subset of proteins that are O-GlcNAcylated during metaphase. As lectins bind glycosylated proteins, we asked if specific lectins interact with mitotic O-GlcNAcylated proteins during metaphase to ensure correct cell division. Galectin-3, a small soluble lectin of the Galectin family, is an excellent candidate, as it has been previously described as a transient centrosomal component in interphase and mitotic epithelial cells. In addition, it has recently been shown to associate with basal bodies in motile cilia, where it stabilizes the microtubule-organizing center (MTOC). Using an experimental mouse model of chronic kidney disease and human epithelial cell lines, we investigate the role of Galectin-3 in dividing epithelial cells. Here we find that Galectin-3 is essential for metaphase where it associates with NuMA in an O-GlcNAcylation-dependent manner. We provide evidence that the NuMA-Galectin-3 interaction is important for mitotic spindle cohesion and for stable NuMA localization to the spindle pole, thus revealing that Galectin-3 is a novel contributor to epithelial mitotic progress

Cystic gene dosage influences kidney lesions after nephron reduction

Cystic kidney disease is characterized by the progressive development of multiple fluid-filled cysts. Cysts can be acquired, or they may appear during development or in postnatal life due to specific gene defects and lead to renal failure. The most frequent form of this disease is the inherited polycystic kidney disease (PKD). Experimental models of PKD showed that an increase of cellular proliferation and apoptosis as well as defects in apico-basal and planar cell polarity or cilia play a critical role in cyst development. However, little is known about the mechanisms and the mediators involved in acquired cystic kidney diseases (ACKD). In this study, we used the nephron reduction as a model to study the mechanisms underlying cyst development in ACKD. We found that tubular dilations after nephron reduction recapitulated most of the morphological features of ACKD. The development of tubular dilations was associated with a dramatic increase of cell proliferation. In contrast, the apico-basal polarity and cilia did not seem to be affected. Interestingly, polycystin 1 and fibrocystin were markedly increased and polycystin 2 was decreased in cells lining the dilated tubules, whereas the expression of several other cystic genes did not change. More importantly, Pkd1 haploinsufficiency accelerated the development of tubular dilations after nephron reduction, a phenotype that was associated to a further increase of cell proliferation. These data were relevant to humans ACKD, as cystic genes expression and the rate of cell proliferation were also increased. In conclusion, our study suggests that the nephron reduction can be considered a suitable model to study ACKD and that dosage of genes involved in PKD is also important in ACKD