Shared and distinct mechanisms of fibrosis

Nature Reviews Rheumatology, Journal Year: 2019, Volume and Issue: 15(12), P. 705 - 730

Published: Nov. 11, 2019

Language: Английский

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Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(9)

Published: Sept. 11, 2021

Abstract Renal fibrosis is a common pathological process that occurs with diverse etiologies in chronic kidney disease. However, its regulatory mechanisms have not yet been fully elucidated. Ferroptosis form of non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. It currently unknown whether ferroptosis initiated during unilateral ureteral obstruction (UUO)-induced renal and role has determined. In this study, we demonstrated induced tubular epithelial cells (TECs) vivo. The inhibitor liproxstatin-1 (Lip-1) reduced iron deposition, death, peroxidation, inhibited the downregulation GPX4 expression UUO, ultimately inhibiting TECs. We found Lip-1 significantly attenuated UUO-induced morphological changes collagen deposition mice. addition, profibrotic factors UUO model. vitro, used RSL3 treatment knocked down level RNAi HK2 to induce ferroptosis. Our results indicated secreted various was able inhibit thereby secretion process. Incubation fibroblasts culture medium from RSL3-induced promoted fibroblast proliferation activation, whereas impeded effects. study may relieve Mechanistically, could reduce activation surrounding paracrine cells. potentially be as therapeutic approach for fibrosis.

Language: Английский

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The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation

Kidney International, Journal Year: 2024, Volume and Issue: 106(2), P. 226 - 240

Published: May 22, 2024

Persistently elevated glycolysis in kidney has been demonstrated to promote chronic disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) mice, as well multiple etiologies of patients with CKD. PFKFB3 expression positively correlated severity fibrosis. Moreover, CKD and mice exhibited increased urinary lactate/creatine levels lactate, respectively. PTC-specific deletion significantly reduced lactate levels, mitigated inflammation fibrosis, preserved function IRI mouse model. Similar protective effects were heterozygous deficiency or those treated inhibitor. Mechanistically, derived from PFKFB3-mediated reprogramming markedly enhanced histone lactylation, particularly H4K12la, which enriched at promoter NF-κB signaling genes like Ikbkb, Rela, Relb, activating their transcription facilitating inflammatory response. Further, inhibited activation IKKβ, I κ B α, p65 kidneys. H4K12la fibrosis These findings suggest may play dual role enhancing by promoting both H4K12la-mediated gene its activation. Thus, targeting pathway could be novel strategy for therapy.

Language: Английский

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Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3086 - 3086

Published: March 7, 2024

Diabetic kidney disease (DKD) is a major cause of chronic (CKD), and it heightens the risk cardiovascular incidents. The pathogenesis DKD thought to involve hemodynamic, inflammatory, metabolic factors that converge on fibrotic pathway. Genetic predisposition unhealthy lifestyle practices both play significant role in development progression DKD. In spite recent emergence angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid antagonists (NS-MRAs), current therapies still fail effectively arrest Glucagon-like peptide 1 receptor agonists (GLP-1RAs), promising class agents, possess potential act as renal protectors, slowing Other including pentoxifylline (PTF), selonsertib, baricitinib hold great promise for due their anti-inflammatory antifibrotic properties. Multidisciplinary treatment, encompassing modifications drug therapy, can decelerate Based treatment heart failure, recommended use multiple drugs combination rather than single-use Unearthing mechanisms underlying urgent optimize management Inflammatory (including IL-1, MCP-1, MMP-9, CTGF, TNF-a TGF-β1), along with lncRNAs, not only serve diagnostic biomarkers, but also therapeutic targets. this review, we delve into We explore additional value combing these develop novel strategies. Drawing from understanding pathogenesis, propose HIF AGE epigenetic targets future.

Language: Английский

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An eCIRP inhibitor attenuates fibrosis and ferroptosis in ischemia and reperfusion induced chronic kidney disease

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 10, 2025

Abstract Background Chronic kidney disease (CKD) is a leading cause of death in the United States, and renal fibrosis represents pathologic hallmark CKD. Extracellular cold-inducible RNA-binding protein (eCIRP) stress response involved acute inflammation, tissue injury regulated cell death. However, role eCIRP chronic inflammation has not been elucidated. We hypothesize that ischemia/reperfusion (RIR)-induced CKD C23, an antagonist to eCIRP, beneficial attenuating ferroptosis RIR-induced Methods C57BL/6 (WT) or CIRP −/− mice underwent with total blockage blood perfusion by clamping bilateral pedicles for 28 min. In WT at time reperfusion, they were treated C23 (8 mg/kg) vehicle. Blood kidneys harvested further analysis 21 days thereafter. separate cohort, RIR treatment vehicle then subjected left nephrectomy 72 h Mice monitored additional 19 days, glomerular filtration rate (GFR) was assessed using noninvasive transcutaneous method. Results CKD, showed decreased collagen deposition, fibronectin staining, as compared mice. Administration ameliorated decreasing expression active TGF-β1, α-SMA, macrophage infiltration kidneys. Furthermore, intervention significantly reducing iron accumulation, increasing glutathione peroxidase 4 (GPX4) lipid peroxidation Treatment also attenuated BUN creatinine. Finally, GFR partially prevented their decrease. Conclusion Our data show plays important alleviated fibrosis, inhibited

Language: Английский

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microRNA Crosstalk Influences Epithelial-to-Mesenchymal, Endothelial-to-Mesenchymal, and Macrophage-to-Mesenchymal Transitions in the Kidney

Frontiers in Pharmacology, Journal Year: 2019, Volume and Issue: 10

Published: Aug. 16, 2019

microRNAs (miRNAs) are small, non-coding nucleotides that regulate diverse biological processes. Altered microRNA biosynthesis or regulation contribute to pathological processes including kidney fibrosis. Kidney fibrosis is characterized by deposition of excess extracellular matrix (ECM) which caused infiltration immune cells, inflammatory altered chemokines, cytokines and activation accumulation fibroblasts in the kidney. These activated can arise from epithelial cells via epithelial-to-mesenchymal transition (EMT), bone marrow-derived M2 phenotype macrophages macrophage-to-mesenchymal (MMT), endothelial endothelial-to-mesenchymal (EndMT), resident monocytes play a crucial role fibrotic events. Disrupted aberrant contributes mesenchymal programs miR-29 regulates interaction between dipeptidyl peptidase-4 (DPP-4) integrin β1 associated active transforming growth factor β (TGFβ) pro-EndMT signaling; however, miR-let-7 targets receptors (TGFRs) inhibit TGF signaling. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) an endogenous anti-fibrotic peptide, with fibroblast receptor 1 (FGFR1) phosphorylation subsequently responsible for production miR-let-7. family clusters participate crosstalk mechanisms, cell homeostasis. The physiological level AcSDKP vital mechanisms restoration suppression profibrotic signaling mitigating DPP-4-associated macrophages. present review highlights recent advancements understanding both development disease as well their potential novel therapeutic states.

Language: Английский

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Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11857 - 11857

Published: Nov. 1, 2021

Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage renal disease. The natural history DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated filtration rate, and, ultimately, failure. It known that associated with metabolic changes caused by hyperglycemia, resulting in hypertrophy, glomerulosclerosis, tubulointerstitial inflammation fibrosis. Hyperglycemia also to programmed epigenetic modification. However, detailed mechanisms involved onset progression remain elusive. In this review, we discuss recent advances regarding pathogenic DKD.

Language: Английский

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Senolytic therapy ameliorates renal fibrosis postacute kidney injury by alleviating renal senescence

The FASEB Journal, Journal Year: 2020, Volume and Issue: 35(1)

Published: Dec. 24, 2020

Acute kidney injury (AKI) is a common clinical problem, and patients who survive AKI have high risk of chronic disease (CKD). The mechanism CKD post-AKI, characterized by progressive renal fibrosis, still unclear. Maladaptive tubular epithelial cells (TECs) after are considered leading cause fibrosis post-AKI. TECs under maladaptive repair manifest characteristics senescence. Removing senescent genetic ablation has been proven effective in reducing fibrosis. Senolytics, which eliminate pharmacological intervention, studied series degenerative diseases. To our knowledge, the effects senolytics on post-AKI not verified before. Here, we confirmed senescence unilateral ischemia/reperfusion murine model. Senescent could activate fibroblasts specifically induced apoptosis TECs. Next, demonstrated that reduce ameliorate both multiple-cisplatin-treatment models. Our results indicate as vital factor progression, senolytic therapy might be promising for treating

Language: Английский

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DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 18, 2020

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation proximal tubular DsbA-L for tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found a tubules-specific knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, cell apoptosis inflammation. Mechanistically, interacted with Hsp90 mitochondria BUMPT cells which activated signaling Smad3 p53 to produce connective tissue growth factor (CTGF) then resulted accumulation ECM kidney fibroblasts. addition, progression TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, repeated acute low-dose cisplatin was also alleviated PT-DsbA-L-KO mice via activation /Smad3 p53/CTGF axis. Finally, above molecular changes were verified biopsies from patients obstructive (Ob). Together, these results suggest promotes

Language: Английский

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IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

British Journal of Pharmacology, Journal Year: 2020, Volume and Issue: 177(8), P. 1695 - 1708

Published: Feb. 5, 2020

Fibrosis is a pathophysiological hallmark of cardiorenal disease. In the heart, fibrosis leads to contractile dysfunction and arrhythmias; in kidney, it final common pathway for many diseases predicts end-stage renal failure. Despite this, there are currently no specific anti-fibrotic treatments available cardiac or Recently unexpectedly, IL-11 was found be major importance fibroblast activation fibrosis. mouse models, overexpression caused heart kidney while genetic deletion Il11ra1 protected against preserved organ function. Neutralizing antibodies IL-11RA have been developed that activity human fibroblasts protect murine models While biology has little studied and, we suggest, largely misunderstood, its autocrine myofibroblasts appears non-redundant fibrosis, which offers new opportunities better understand potentially target

Language: Английский

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