Morphological changes in the fetal kidney induced by exposure to fluoride during pregnancy.

To determine if fluoride's established negative impact on adult kidney health begins during gestation, an intergenerational model of Wistar rats was exposed to two doses of fluoride (2.5 or 5.0 mg/kg/day via gavage) 20 days before mating and during gestation (20 days).

Holistic exploration of and hsa-miR-137 in colorectal cancer via multi-omic data Integration.

Colorectal cancer (CRC) ranks among the most widespread malignancies globally, with early detection significantly influencing prognosis. Employing a systems biology approach, we aimed to unravel the intricate mRNA-miRNA network linked to CRC pathogenesis, potentially yielding diagnostic biomarkers. Through an integrative analysis of microarray, Bulk RNA-seq, and single-cell RNA-seq data, we explored CRC-related transcriptomes comprehensively.

Identification of inflammatory biomarkers in IgA nephropathy using the NanoString technology: a validation study in Caucasians.

Objective And Design: Immunoglobulin A nephropathy (IgAN) is a kidney disease characterized by the accumulation of IgA deposits in the glomeruli of the kidney, leading to inflammation and damage to the kidney. The inflammatory markers involved in IgAN remain to be defined. Gene expression analysis platforms, such as the NanoString nCounter system, are promising screening and diagnostic tools, especially in oncology.

Tungsten toxicity on kidney tubular epithelial cells induces renal inflammation and M1-macrophage polarization.

Tungsten is widely used in medical, industrial, and military applications. The environmental exposure to tungsten has increased over the past several years, and few studies have addressed its potential toxicity. In this study, we evaluated the effects of chronic oral tungsten exposure (100 ppm) on renal inflammation in male mice.

Advancing Discovery Research in Nephrology in Canada: A Conference Report From the 2021 Molecules and Mechanisms Mediating Kidney Health and Disease (M3K) Scientific Meeting and Investigator Summit.

Purpose Of Conference: New discoveries arising from investigations into fundamental aspects of kidney development and function in health and disease are critical to advancing kidney care. Scientific meetings focused specifically on fundamental biology of the kidney can facilitate interactions, support the development of collaborative groups, and accelerate translation of key findings. The Canadian fundamental kidney researcher community has lacked such a forum.

Seq2Neo: A Comprehensive Pipeline for Cancer Neoantigen Immunogenicity Prediction.

Neoantigens derived from somatic DNA alterations are ideal cancer-specific targets. In recent years, the combination therapy of PD-1/PD-L1 blockers and neoantigen vaccines has shown clinical efficacy in original PD-1/PD-L1 blocker non-responders. However, not all somatic DNA mutations result in immunogenicity among cancer cells and efficient tools to predict the immunogenicity of neoepitopes are still urgently needed.

SMOC2 promotes an epithelial-mesenchymal transition and a pro-metastatic phenotype in epithelial cells of renal cell carcinoma origin.

Renal Cell Carcinoma (RCC) is the most common form of all renal cancer cases, and well-known for its highly aggressive metastatic behavior. SMOC2 is a recently described non-structural component of the extracellular matrix (ECM) that is highly expressed during tissue remodeling processes with emerging roles in cancers, yet its role in RCC remains elusive. Using gene expression profiles from patient samples, we identified SMOC2 as being significantly expressed in RCC tissue compared to normal renal tissue, which correlated with shorter RCC patient survival.

The non-steroidal mineralocorticoid receptor antagonist finerenone is a novel therapeutic option for patients with Type 2 diabetes and chronic kidney disease.

Despite strong preclinical data supporting the use of mineralocorticoid receptor antagonists (MRAs) to provide cardiorenal protection in rodent models of diabetes, the clinical evidence of their utility in treating chronic kidney disease (CKD) has been limited. Two major clinical trials (FIDELIO-DKD and FIGARO-DKD) including more than 13,000 patients with albuminuric CKD and Type 2 diabetes randomized to placebo or finerenone (MRA) have recently provided exciting results showing a significant risk reduction for kidney and cardiovascular outcomes. In this review, we will summarize the major findings of these trials, together with post-hoc and pooled analyses that have allowed evaluation of the efficacy and safety of finerenone across the spectrum of CKD, revealing significant protective effects of finerenone against kidney failure, new-onset atrial fibrillation or flutter, new-onset heart failure, cardiovascular death, and first and total heart-failure hospitalizations.

Subchronic oral exposure of tungsten induces myofibroblast transformation and various markers of kidney fibrosis.

Tungsten is a naturally occurring transition element used in a broad range of applications. As a result of its extensive use, we are increasingly exposed to tungsten from our environment, including potable water, since tungsten can become bioaccessible in ground sources. The kidneys are particularly susceptible to tungsten exposure as this is the main site for tungsten excretion.

Alk1 haploinsufficiency causes glomerular dysfunction and microalbuminuria in diabetic mice.

Endothelial dysfunction has been shown to play an important role in the pathogenesis of glomerular damage during diabetic kidney disease (DKD). As such, a better understanding of the molecular mechanisms involved in glomerular endothelial dysfunctions could provide novel therapeutic strategies for the prevention of DKD. We have previously shown that Alk1/BMP9 signaling plays an important function to maintain vascular integrity in diabetic animals.

Emerging Roles of Matricellular Proteins in Systemic Sclerosis.

Systemic sclerosis is a rare chronic heterogenous disease that involves inflammation and vasculopathy, and converges in end-stage development of multisystem tissue fibrosis. The loss of tight spatial distribution and temporal expression of proteins in the extracellular matrix (ECM) leads to progressive organ stiffening, which is a hallmark of fibrotic disease. A group of nonstructural matrix proteins, known as matricellular proteins (MCPs) are implicated in dysregulated processes that drive fibrosis such as ECM remodeling and various cellular behaviors.

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment.

The extracellular matrix (ECM) surrounding cells is indispensable for regulating their behavior. The dynamics of ECM signaling are tightly controlled throughout growth and development. During tissue remodeling, matricellular proteins (MCP) are secreted into the ECM.

Characterization of Matricellular Protein Expression Signatures in Mechanistically Diverse Mouse Models of Kidney Injury.

Fibrosis is the most common pathophysiological manifestation of Chronic Kidney Disease (CKD). It is defined as excessive deposition of extracellular matrix (ECM) proteins. Embedded within the ECM are a family of proteins called Matricellular Proteins (MCPs), which are typically expressed during chronic pathologies for ECM processing.

Found in Translation: Reasons for Optimism in the Pursuit to Prevent Chronic Kidney Disease After Acute Kidney Injury.

Purpose Of Review: The current review will discuss on the progress of studying the transition phase between acute kidney injury (AKI) and chronic kidney disease (CKD) through improved animal models, common AKI and CKD pathways, and how human studies may inform different translational approaches.

Sources Of Information: PubMed and Google Scholar.

Methods: A narrative review was performed using the main terms "acute kidney injury," "chronic kidney disease," "end-stage renal disease," "animal models," "review," "decision-making," and "translational research.

Targeting Phospholipase D4 Attenuates Kidney Fibrosis.

Phospholipase D4 (PLD4), a single-pass transmembrane glycoprotein, is among the most highly upregulated genes in murine kidneys subjected to chronic progressive fibrosis, but the function of PLD4 in this process is unknown. Here, we found PLD4 to be overexpressed in the proximal and distal tubular epithelial cells of murine and human kidneys after fibrosis. Genetic silencing of PLD4, either globally or conditionally in proximal tubular epithelial cells, protected mice from the development of fibrosis.

Silencing SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast transformation.

Secreted modular calcium-binding protein 2 (SMOC2) belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins whose members are known to modulate cell-matrix interactions. We report that SMOC2 is upregulated in the kidney tubular epithelial cells of mice and humans following fibrosis. Using genetically manipulated mice with SMOC2 overexpression or knockdown, we show that SMOC2 is critically involved in the progression of kidney fibrosis.

Myofibroblast repair mechanisms post-inflammatory response: a fibrotic perspective.

Introduction: Fibrosis is a complex chronic disease characterized by a persistent repair response. Its pathogenesis is poorly understood but it is typically the result of chronic inflammation and maintained with the required activity of transforming growth factor-β (TGFβ) and extracellular matrix (ECM) tension, both of which drive fibroblasts to transition into a myofibroblast phenotype.

Findings: As the effector cells of repair, myofibroblasts migrate to the site of injury to deposit excessive amounts of matrix proteins and stimulate high levels of contraction.

AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex.

Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity.

Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex: IMPLICATION OF A NOVEL MDMX SER-314 PHOSPHOSITE.

Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes.

Prostaglandin E2-Dependent Phosphorylation of RAS Inhibition 1 (RIN1) at Ser 291 and 292 Inhibits Transforming Growth Factor-β-Induced RAS Activation Pathway in Human Synovial Fibroblasts: Role in Cell Migration.

Prostaglandin E2 (PGE2 )-stimulated G-protein-coupled receptor (GPCR) activation inhibits pro-fibrotic TGFβ-dependent stimulation of human fibroblast to myofibroblast transition (FMT), though the precise molecular mechanisms are not fully understood. In the present study, we describe the PGE2 -dependent suppression and reversal of TGFβ-induced events such as α-sma expression, stress fiber formation, and Ras/Raf/ERK/MAPK pathway-dependent activation of myofibroblast migration. In order to elucidate post-ligand-receptor signaling pathways, we identified a predominant PKA phosphorylation motif profile in human primary fibroblasts after treatment with exogenous PGE2 (EC50 30 nM, Vmax 100 nM), mimicked by the adenyl cyclase activator forskolin (EC50 5 μM, Vmax 10 μM).

Quantitative phosphoproteomic analysis of signaling downstream of the prostaglandin e2/g-protein coupled receptor in human synovial fibroblasts: potential antifibrotic networks.

The Prostaglandin E2 (PGE2) signaling mechanism within fibroblasts is of growing interest as it has been shown to prevent numerous fibrotic features of fibroblast activation with limited evidence of downstream pathways. To understand the mechanisms of fibroblasts producing tremendous amounts of PGE2 with autocrine effects, we apply a strategy of combining a wide-screening of PGE2-induced kinases with quantitative phosphoproteomics. Our large-scale proteomic approach identified a PKA signal transmitted through phosphorylation of its substrates harboring the R(R/X)X(S*/T*) motif.

Prostaglandin E(2)-dependent blockade of actomyosin and stress fibre formation is mediated through S1379 phosphorylation of ROCK2.

Prostaglandin E2 is a pleiotropic bioactive lipid that controls cytoskeletal alterations, although the precise G-protein coupled EP receptor signalling mechanisms remain ill defined. We adopted a phosphoproteomic approach to characterize post-receptor downstream signalling substrates using antibodies that selectively recognize and immunoprecipitate phosphorylated substrates of a number of kinases. Using human synovial fibroblasts in monolayer cell culture, PGE2 induced rapid and sustained changes in cellular morphology and reduction in cytoplasmic volume that were associated with disassembly of the phalloidin-stained stress fibres as judged by light and confocal microscopy.

Reversible blockade of thymic output: an inherent part of TLR ligand-mediated immune response.

TLRs constitute a first set of sensors that detect viral nucleic acids including dsRNA which triggers TLR3. We report the early, direct, and detrimental effect of polyinosine-polycytidilic acid treatment on T cell development. Inhibition of thymopoiesis was targeted to several thymocyte subpopulations.