Kidney fibrosis: from mechanisms to therapeutic medicines

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 17, 2023

Abstract Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading scarring, a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. fibrosis identified tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, vascular rarefaction. Fibrotic niche, where organ initiates, complex interplay between injured parenchyma (like tubular cells) multiple non-parenchymal cell lineages (immune mesenchymal located spatially within scarring areas. Although the mechanisms are complicated due kinds cells involved, with help single-cell technology, many key questions have been explored, such as what kind renal tubules profibrotic, myofibroblasts originate, which immune how communicate each other. In addition, genetics epigenetics deeper that regulate fibrosis. And reversible nature epigenetic changes including DNA methylation, RNA interference, chromatin remodeling, gives an opportunity stop or reverse therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) developed delay progression recent years. Furthermore, better understanding also favored discover biomarkers fibrotic injury. review, we update advances mechanism summarize novel treatment for CKD.

Language: Английский

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Discovery and validation of miR-452 as an effective biomarker for acute kidney injury in sepsis

Theranostics, Journal Year: 2020, Volume and Issue: 10(26), P. 11963 - 11975

Published: Jan. 1, 2020

Rationale: Sepsis is the cause of nearly half acute kidney injury (AKI) and, unfortunately, AKI in sepsis associated with unacceptably high rates mortality. Early detection would guide timely intervention and care patients. Currently, NephroCheck, based on urinary [TIMP2]*[IGFBP7], only FDA approved test for early AKI, which has a relatively low sensitivity Methods:In vitro, BUMPT (Boston University mouse proximal tubular cell line) cells were treated lipopolysaccharides (LPS). In vivo, was induced mice by LPS injection or cecal ligation puncture (CLP). To validate biomarker potential miR-452, serum samples collected from 47 patients 50 without 10 healthy subjects. Results: miR-452 renal septic induction shown to be mediated NF-κB. Notably, increased following CLP treatment, prior detectable dysfunction tissue damage. had significantly higher levels than AKI. Spearman's demonstrated remarkable positive correlation between creatinine (r=0.8269). The area under receiver operating characteristic curve (AUC) 0.8985 miR-452. Logistic regression analysis showed striking 72.48-fold increase risk every 1-fold reached 87.23%, notably 61.54% achieved while specificity (78.00%) slightly lower that [TIMP2]*[IGFBP7] (87.18%). Conclusions: via NF-κB especially urine, may an effective

Language: Английский

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miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation

Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 34(8), P. 1381 - 1397

Published: May 22, 2023

Cold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST remains poorly understood, and effective therapies are not available. This study has demonstrated an important role microRNAs revealed changes microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during mice dysfunctional grafts humans. Mechanistically, NDUFA4 (a key component mitochondrial respiration complex) identified as a direct target miR-147. By repressing NDUFA4, miR-147 induces damage tubular cell death. Blockade overexpression reduce improve graft function, unveiling new therapeutic targets kidney transplantation.

Language: Английский

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The role of epithelial cells in fibrosis: Mechanisms and treatment

Pharmacological Research, Journal Year: 2024, Volume and Issue: 202, P. 107144 - 107144

Published: March 13, 2024

Fibrosis is a pathological process that affects multiple organs and considered one of the major causes morbidity mortality in diseases, resulting an enormous disease burden. Current studies have focused on fibroblasts myofibroblasts, which directly lead to imbalance generation degradation extracellular matrix (ECM). In recent years, increasing number role epithelial cells fibrosis. some cases, are first exposed external physicochemical stimuli may drive collagen accumulation mesenchyme. other source stimulation mainly immune cytokines, similarly altered process. this review, we will focus dynamic alterations involved after injury during fibrogenesis, discuss association among them, summarize therapies targeting changed cells. Especially, mesenchymal transition (EMT) key central step, closely linked biological behaviors. Meanwhile, think disruption barrier, cell death basal stem populations stemness fibrosis not appreciated. We believe targeted can prevent progress fibrosis, but reverse it. The provide wonderful preventive delaying action.

Language: Английский

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A systematic review of epigenetic interplay in kidney diseases: Crosstalk between long noncoding RNAs and methylation, acetylation of chromatin and histone

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116922 - 116922

Published: June 13, 2024

The intricate crosstalk between long noncoding RNAs (lncRNAs) and epigenetic modifications such as chromatin/histone methylation acetylation offer new perspectives on the pathogenesis treatment of kidney diseases. lncRNAs, a class transcripts longer than 200 nucleotides with no protein-coding potential, are now recognized key regulatory molecules influencing gene expression through diverse mechanisms. They modulate by recruiting or blocking enzymes responsible for adding removing methyl acetyl groups, DNA, N6-methyladenosine (m6A) histone acetylation, subsequently altering chromatin structure accessibility. In diseases acute injury (AKI), chronic disease (CKD), diabetic nephropathy (DN), glomerulonephritis (GN), renal cell carcinoma (RCC), aberrant patterns DNA/RNA/histone have been associated onset progression, revealing complex interplay lncRNA dynamics. Recent studies highlighted how lncRNAs can impact pathology affecting function genes involved in cycle control, fibrosis, inflammatory responses. This review will separately address roles diseases, particular emphasis elucidating bidirectional effects underlying mechanisms conjunction addition to potential exacerbating renoprotective pathologies. Understanding reciprocal relationships not only shed light molecular underpinnings pathologies but also present avenues therapeutic interventions biomarker development, advancing precision medicine nephrology.

Language: Английский

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Circular RNA VMA21 ameliorates sepsis‐associated acute kidney injury by regulating miR‐9‐3p/SMG1/inflammation axis and oxidative stress

Journal of Cellular and Molecular Medicine, Journal Year: 2020, Volume and Issue: 24(19), P. 11397 - 11408

Published: Aug. 22, 2020

Abstract Accumulating evidence suggests that circular RNAs have the abilities to regulate gene expression during progression of sepsis‐associated acute kidney injury. Circular RNA VMA21 (circVMA21), a recent identified RNA, could reduce apoptosis alleviate intervertebral disc degeneration in rats and protect WI‐38 cells from lipopolysaccharide‐induced However, role circVMA21 injury (sepsis‐associated AKI) is unknown. In this study, we first demonstrated alleviated AKI by reducing inflammation HK‐2 cells. Additionally, explore molecule mechanism underlying amelioration, after bioinformatics analysis, confirmed miR‐9‐3p directly bound luciferase immunoprecipitation assay, effector protein was SMG1. Furthermore, oxidative stress caused down‐regulated circVMA21. conclusion, plays an important regulating via adjusting miR‐9‐39/SMG1/inflammation axis stress.

Language: Английский

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The negative feedback loop of NF-κB/miR-376b/NFKBIZ in septic acute kidney injury

JCI Insight, Journal Year: 2020, Volume and Issue: 5(24)

Published: Dec. 16, 2020

Sepsis is the leading cause of acute kidney injury (AKI). However, pathogenesis septic AKI remains largely unclear. Here, we demonstrate a significant decrease microRNA-376b (miR-376b) in renal tubular cells mice with AKI. Urinary miR-376b these was also dramatically decreased. Patients sepsis had significantly lower urinary than patients without AKI, supporting its diagnostic value for LPS treatment led to activation NF-κB, and inhibition NF-κB prevented miR-376b. ChIP assay further verified binding gene promoter upon treatment. Functionally, mimics exaggerated cell death, injury, intrarenal production inflammatory cytokines, while inhibiting afforded protective effects mice. Interestingly, suppressed expression inhibitor ζ (NFKBIZ) both vitro vivo models Luciferase microRNA target reporter NFKBIZ as direct Collectively, results illustrate NF-κB/miR-376b/NFKBIZ negative feedback loop that regulates inflammation damage Moreover, potential biomarker diagnosis sepsis.

Language: Английский

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AGE/RAGE signaling-mediated endoplasmic reticulum stress and future prospects in non-coding RNA therapeutics for diabetic nephropathy

Biomedicine & Pharmacotherapy, Journal Year: 2020, Volume and Issue: 131, P. 110655 - 110655

Published: Aug. 24, 2020

Disturbance of endoplasmic reticulum (ER) homeostasis triggered by the accumulation unfolded proteins and advanced glycation end-products (AGEs) plays a major role in pathophysiology diabetic nephropathy. Activation receptor for AGEs (RAGE) stimulates NADPH oxidase-mediated reactive oxygen species (ROS) production, leading to ER stress, inflammation, glomerular hypertrophy, podocyte injury, renal fibrosis. A growing body evidence indicates that non-coding RNAs (ncRNAs) could rescue stress inflammation epigenetic modification. This review summarizes ncRNA regulation AGE/RAGE signaling-mediated discusses opportunities challenges ncRNA-loaded extracellular vesicle therapy

Language: Английский

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MiR-150-5p protects against septic acute kidney injury via repressing the MEKK3/JNK pathway

Cellular Signalling, Journal Year: 2021, Volume and Issue: 86, P. 110101 - 110101

Published: July 30, 2021

Language: Английский

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Circ_0114428 Regulates Sepsis-Induced Kidney Injury by Targeting the miR-495-3p/CRBN Axis

Inflammation, Journal Year: 2021, Volume and Issue: 44(4), P. 1464 - 1477

Published: April 8, 2021

Language: Английский

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