Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 12, 2024

Abstract Renal proximal tubule epithelial cells have considerable intrinsic repair capacity following injury. However, a fraction of injured fails to undergo normal and assumes proinflammatory profibrotic phenotype that may promote fibrosis chronic kidney disease. The healthy failed change is marked by cell state-specific transcriptomic epigenomic changes. Single nucleus joint RNA- ATAC-seq sequencing offers an opportunity study the gene regulatory networks underpinning these changes in order identify key drivers. We develop regularized regression approach construct genome-wide parametric using multiomic datasets. generate single dataset from seven adult human samples apply our method drivers injury response associated with demonstrate highly effective tool for predicting cis- trans- elements transition use it NFAT5 as driver maladaptive state.

Language: Английский

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STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(3)

Published: March 14, 2024

Abstract Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged a critical component immune inflammatory responses. However, role STING in pathogenesis septic AKI remains unclear. This study demonstrated that was significantly activated tubular cells induced lipopolysaccharide (LPS) vivo vitro. Tubule-specific knockout attenuated LPS-induced renal dysfunction pathological changes. Mechanistically, pathway promotes NOD-like receptor protein 3 (NLRP3) activation. triggers endoplasmic reticulum (ER) stress induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting activation association with NLRP3. Eventually, NLRP3 inflammasome leads cell pyroptosis. revealed STING-regulated network further identified STING/ER stress/mtROS/NLRP3 axis an emerging contributing damage AKI. Hence, targeting may be promising therapeutic strategy preventing

Language: Английский

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Role of mitochondria in pathogenesis and therapy of renal fibrosis

Metabolism, Journal Year: 2024, Volume and Issue: 155, P. 155913 - 155913

Published: April 11, 2024

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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Nutritional and Metabolic Control of Ferroptosis

Annual Review of Nutrition, Journal Year: 2022, Volume and Issue: 42(1), P. 275 - 309

Published: June 2, 2022

Ferroptosis is a type of regulated cell death characterized by an excessive lipid peroxidation cellular membranes caused the disruption antioxidant defense system and/or imbalanced metabolism. differentiates from other forms in that several metabolic pathways and nutritional aspects, including endogenous antioxidants (such as coenzyme Q10, vitamin E, di/tetrahydrobiopterin), iron handling, energy sensing, selenium utilization, amino acids, fatty directly regulate cells' sensitivity to ferroptosis. As hallmarks ferroptosis have been documented variety diseases, neurodegeneration, acute organ injury, therapy-resistant tumors, modulation using pharmacological tools or reprogramming holds great potential for treatment ferroptosis-associated diseases cancer therapy. Hence, this review focuses on regulation cues discusses interventions therapy targeting

Language: Английский

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Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis

Clinical Immunology, Journal Year: 2022, Volume and Issue: 248, P. 109213 - 109213

Published: Dec. 22, 2022

Language: Английский

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Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair

Cell Reports, Journal Year: 2022, Volume and Issue: 41(6), P. 111610 - 111610

Published: Nov. 1, 2022

In both humans and mice, repair of acute kidney injury is worse in males than females. Here, we provide evidence that this sexual dimorphism results from sex differences ferroptosis, an iron-dependent, lipid-peroxidation-driven regulated cell death. Using genetic single-cell transcriptomic approaches report female confers striking protection against which was experimentally induced proximal tubular (PT) cells by deleting glutathione peroxidase 4 (Gpx4). Single-cell analyses further identify the NFE2-related factor 2 (NRF2) antioxidant protective pathway as a resilience mechanism ferroptosis. Genetic inhibition pharmacological activation studies show NRF2 controls PT fate plasticity regulating Importantly, protects male ferroptosis improves cellular Our data highlight potential therapeutic target to prevent failed renal after sexes modulating plasticity.

Language: Английский

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Mechanisms of kidney fibrosis and routes towards therapy

Trends in Endocrinology and Metabolism, Journal Year: 2023, Volume and Issue: 35(1), P. 31 - 48

Published: Sept. 28, 2023

Language: Английский

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Single-cell transcriptomic profiles in the pathophysiology within the microenvironment of early diabetic kidney disease

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(7)

Published: July 17, 2023

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage disease, resulting in a huge socio-economic impact. Kidney highly complex organ and pathogenesis underlying organization involves cell-to-cell interaction within heterogeneous milieu. Advanced single-cell RNA sequencing (scRNA-seq) could reveal architecture with microenvironment early DKD. We used scRNA-seq to investigate changes db/m mice db/db at 14th week. Uniform Manifold Approximation Projection were applied classify cells into different clusters proper resolution. Weighted gene co-expression network analysis was identify key molecules specifically expressed tubules. Information cell–cell communication obtained using receptor-ligand pairing resources. In vitro model, human subjects, co-detection by indexing staining pathophysiologic role hub genes Among four distinct subsets proximal tubule (PT), lower percentages proliferative PT containing AQP4 expression (PT AQP4+ ) induced impaired cell repair activity dysfunction renin-angiotensin system modulation found that ferroptosis involved DKD progression, ceruloplasmin acted as central regulator induction . addition, thick ascending limbs collecting ducts metabolism function also critical pathogenic features mice. Secreted phosphoprotein 1 (SPP1) mediated cross-talk tubular microenvironment, validated correlation between urinary SPP1/Cr level injury. Finally, mesangial cell-derived semaphorin 3C (SEMA3C) further promoted endothelium-mesenchymal transition glomerular endothelial through NRP1 NRP2, SEMA3C/Cr positively correlated These data identified

Language: Английский

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Fibrosis in Pathology of Heart and Kidney: From Deep RNA-Sequencing to Novel Molecular Targets

Circulation Research, Journal Year: 2023, Volume and Issue: 132(8), P. 1013 - 1033

Published: April 13, 2023

Diseases of the heart and kidney, including failure chronic kidney disease, can dramatically impair life expectancy quality patients. The form a functional axis; therefore, impairment 1 organ will inevitably affect function other. Fibrosis represents common final pathway diseases both organs, regardless disease entity. Thus, inhibition fibrosis promising therapeutic approach to treat organs resolve impairment. However, despite growing knowledge in this field, exact pathomechanisms that drive remain elusive. RNA-sequencing approaches, particularly single-cell RNA-sequencing, have revolutionized investigation at molecular level facilitated discovery disease-associated cell types mechanisms. In review, we give brief overview over evolution techniques, summarize most recent insights into pathogenesis fibrosis, discuss how transcriptomic data be used, identify new drug targets develop novel strategies.

Language: Английский

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