Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases.
View Article and Find Full Text PDFProgressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19.
View Article and Find Full Text PDFTubulointerstitial fibrosis is the common pathological substrate for many etiologies leading to chronic kidney disease. Although perturbations in the circadian rhythm have been associated with renal disease, the role of the molecular clock in the pathogenesis of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (unilateral ureteral obstruction, folic acid, and adenine nephrotoxicity), using genetically modified mice with selective deficiencies of the clock components , , and We found that the molecular clock pathway was enriched in damaged tubular epithelial cells with marked metabolic alterations.
View Article and Find Full Text PDFChronic kidney disease (CKD) is characterized by the progressive and irreversible deterioration of kidney function and structure with the appearance of renal fibrosis. A significant decrease in mitochondrial metabolism, specifically a reduction in fatty acid oxidation (FAO) in tubular cells, is observed in tubulointerstitial fibrosis, whereas FAO enhancement provides protection. Untargeted metabolomics offers the potential to provide a comprehensive analysis of the renal metabolome in the context of kidney injury.
View Article and Find Full Text PDFBackground And Aims: PTTG1 is almost undetectable in adult livers but is highly expressed in hepatocarcinoma. While little is known about its involvement in liver fibrosis, PTTG1 expression is associated with DLK1. We assessed the role of the PTTG1/DLK1 pathway in fibrosis progression and the potential therapeutic effect of PTTG1 silencing in fibrosis.
View Article and Find Full Text PDFKidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, there are conceptual and practical challenges to directly targeting kidney fibrosis. Whether fibrosis is mainly a cause or a consequence of CKD progression has been disputed.
View Article and Find Full Text PDFThe metabolic impairment of kidney tubular cells is a key mechanism underlying the pathophysiology of renal fibrosis. In particular, a drastic reduction in fatty acid oxidation is essentially responsible for the global energy failure occurring in the tubulointerstitial compartment. Piret et al.
View Article and Find Full Text PDFAs neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms.
View Article and Find Full Text PDFExcessive accumulation of extracellular matrix (ECM) is the hallmark of fibrotic diseases. In the kidney, it is the final common pathway of prevalent diseases, leading to chronic renal failure. While cytokines such as TGF-β play a fundamental role in myofibroblast transformation, recent work has shown that mitochondrial dysfunction and defective fatty acid oxidation (FAO), which compromise the main source of energy for renal tubular epithelial cells, have been proposed to be fundamental contributors to the development and progression of kidney fibrosis.
View Article and Find Full Text PDFChronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis.
View Article and Find Full Text PDFPreclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms.
View Article and Find Full Text PDFEnvironmental risk factors, including physicochemical agents, noise and mental stress, have a considerable impact on human health. This environmental exposure may lead to epigenetic reprogramming, including changes in non-coding RNAs (ncRNAs) signatures, which can contribute to the pathophysiology state. Oxidative stress is one of the results of this environmental disturbance by modifying cellular processes such as apoptosis, signal transduction cascades, and DNA repair mechanisms.
View Article and Find Full Text PDFNefrologia (Engl Ed)
October 2021
MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression through post-transcriptional repression of their target messenger RNAs. A study of changes in expression of certain miRNAs in the kidney has supplied evidence on their pathogenic role and therapeutic potential in nephrology. This review proposes a nanotechnology approach based on the binding of analogs or inhibitors of miRNAs formed by peptide nucleic acids (PNAs) to peptides with a transmembrane structure sensitive to a low pH, called pHLIPs (pH [low] insertion peptides).
View Article and Find Full Text PDFDespite the recent advances in the standardization of untargeted metabolomics workflows, there is still a lack of attention to specific data treatment strategies that require deep knowledge of the biological problem and need to be applied after a well-thought out process to understand the effect of the practice. One of those strategies is data normalization. Data-driven assumptions are critical especially addressing unwanted variation present in the biological model as it can be the case in heterogeneous tissues, cells with different sizes or biofluids with different concentrations.
View Article and Find Full Text PDFChronic kidney disease (CKD) is a devastating condition that is reaching epidemic levels owing to the increasing prevalence of diabetes mellitus, hypertension and obesity, as well as ageing of the population. Regardless of the underlying aetiology, CKD is slowly progressive and leads to irreversible nephron loss, end-stage renal disease and/or premature death. Factors that contribute to CKD progression include parenchymal cell loss, chronic inflammation, fibrosis and reduced regenerative capacity of the kidney.
View Article and Find Full Text PDFMicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO).
View Article and Find Full Text PDFPrevious work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation.
View Article and Find Full Text PDFAims: Myocardial fibrosis is associated with profound changes in ventricular architecture and geometry, resulting in diminished cardiac function. There is currently no information on the role of the delta-like homologue 1 (Dlk1) in the regulation of the fibrotic response. Here, we investigated whether Dlk1 is involved in cardiac fibroblast-to-myofibroblast differentiation and regulates myocardial fibrosis and explored the molecular mechanism underpinning its effects in this process.
View Article and Find Full Text PDFGlutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice).
View Article and Find Full Text PDFSignificance: MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on every realm of biomedicine is established and progressively increasing. The impact of environment on human health is enormous.
View Article and Find Full Text PDFFibrogenesis Tissue Repair
June 2016
Background: Excessive accumulation of extracellular matrix (ECM) proteins is the hallmark of fibrotic diseases, including skin fibrosis. This response relies on the activation of dermal fibroblasts that evolve into a pro-fibrogenic phenotype. One of the major players in this process is the cytokine transforming growth factor-β (TGF-β).
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