Exosomes secreted by ATF3/Nrf2-mediated ferroptotic renal tubular epithelial cells promote M1/M2 ratio imbalance inducing renal interstitial fibrosis following ischemia and reperfusion injury DOI Creative Commons
Qiao Tang, Jiǎtāo Xiè, Yifei Wang

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 5, 2025

Background Severe renal ischemia and reperfusion injury (IRI) progresses to interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis macrophage polarization both play important roles in this model, their specific pathogenesis interactions have not been elucidated. Therefore, we aimed explore the mechanisms by which ferrotosis occurs tubular epithelial cells (RTECs) ferroptotic cell-derived exosomes induce IRI-related RIF model. Methods In vivo , C57BL/6J mice were randomly divided into four groups: sham group, (IR) IR + Ferrostatin-1 (Fer-1) +ATF3 knockdown (ATF KD ) group. vitro RTECs control (CON) hypoxia/reoxygenation (HR) HR +Fer-1 siRNA-ATF3 (siATF3) Result Compared group showed more severe kidney HE staining, collagen fibers Masson higher α-SMA expression levels immunohistochemistry. Total iron MDA content increased while GSH decreased. The had significant mitochondrial damage PTGS2 TFRC mRNA than those above indexes all alleviated IR+Fer-1 or IR+ATF3 groups. addition, protein expressions of ATF3, Nrf2 HO-1 ATF3 groups decreased, contents further increased. Moreover, there M2 markers (Arg1, TGF-β IL-10 mRNA) lower compared results experiment are consistent experiment. Mechanistically, release carrying miR-1306-5p promoted macrophage. Conclusion might accelerate ferroptosis inhibiting Nrf2/ARE pathway, from reduced M1/M2 ratio, promoting fibrosis.

Language: Английский

Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair DOI Creative Commons
Shintaro Ide, Kana Ide, Koki Abe

et al.

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

Citations

48
Mechanisms of kidney fibrosis and routes towards therapy DOI
N. Yamashita, Rafael Kramann

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

Published: Sept. 28, 2023

Language: Английский

Citations

32
Fibrosis in Pathology of Heart and Kidney: From Deep RNA-Sequencing to Novel Molecular Targets DOI Open Access
Felix Schreibing, Teresa M Anslinger, Rafael Kramann

et al.

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

Citations

29
Inhibition of ACSL4 ameliorates tubular ferroptotic cell death and protects against fibrotic kidney disease DOI Creative Commons
Yue Dai, Yuting Chen,

Dexiameng Mo

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Sept. 5, 2023

Ferroptosis is a recently recognized form of regulated cell death, characterized by iron-dependent accumulation lipid peroxidation. Ample evidence has depicted that ferroptosis plays an essential role in the cause or consequence human diseases, including cancer, neurodegenerative disease and acute kidney injury. However, exact underlying mechanism fibrotic remain unknown. Acyl-CoA synthetase long-chain family member 4 (ACSL4) been demonstrated as component execution shaping composition. In this study, we aim to discuss potential ACSL4-mediated tubular epithelial cells (TECs) during renal fibrosis. The unbiased gene expression studies showed ACSL4 was tightly associated with decreased function progression To explore kidney, specific inhibitor rosiglitazone (ROSI) used disturb high TECs induced TGF-β, unilateral ureteral obstruction (UUO) fatty acid (FA)-modeled mice vivo, siRNA knockdown TGF-β-induced HK2 vitro. results inhibition effectively attenuated occurrence alleviated interstitial response. addition, various profibrotic cytokines all after ROSI-treated vivo Further investigation obviously attenuates fibrosis reducing proferroptotic precursors arachidonic acid- adrenic containing phosphatidylethanolamine (AA-PE AdA-PE). conclusion, these suggest for ferroptotic death development viable therapeutic approach preventing diseases.

Language: Английский

Citations

28
High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing DOI Creative Commons
Hao Wu, Eryn E. Dixon, Qiao Xuanyuan

et al.

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

Published: Feb. 15, 2024

Abstract Emerging spatially resolved transcriptomics technologies allow for the measurement of gene expression in situ at cellular resolution. We apply direct RNA hybridization-based sequencing (dRNA HybISS, Cartana part 10xGenomics) to compare male and female healthy mouse kidneys kidney injury repair timecourse. A pre-selected panel 200 genes is used identify cell state dynamics patterns during repair. develop a new computational pipeline, CellScopes, rapid analysis, multi-omic integration visualization transcriptomic datasets. The resulting dataset allows us resolve 13 types within distinct niches, dynamic alterations over course cell-cell interactions between leukocytes parenchyma. At late timepoints after injury, C3+ are enriched near pro-inflammatory, failed-repair proximal tubule cells. Integration snRNA-seq from same samples also impute spatial localization not directly measured by dRNA HybISS.

Language: Английский

Citations

16
Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress DOI
Kuo Du, Liuyang Wang, Ji Hye Jun

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(7), P. 949 - 968

Published: June 25, 2024

Language: Английский

Citations

16
Role of ferroptosis in chronic kidney disease DOI Creative Commons
Shiyang Li, Qiuxia Han, Chang Liu

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 12, 2024

Abstract Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with gradual loss renal function, incidence various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt progression injury in emphasizing urgent need delve into precise molecular mechanisms governing occurrence development CKD while identifying novel therapeutic targets. Renal fibrosis, typical pathological feature plays pivotal role disrupting normal structures function. Ferroptosis recently discovered iron-dependent form cell death characterized by lipid peroxide accumulation. emerged potential key player diseases initiation organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute intricate interplay between its progression. This review comprehensively outlines relationship terms iron metabolism peroxidation, discusses current landscape pharmacological research on ferroptosis, shedding light promising avenues for intervention. It further illustrates recent breakthroughs ferroptosis-related regulatory implicated thereby providing new insights treatment.

Language: Английский

Citations

15
Spatial transcriptomics defines injury specific microenvironments and cellular interactions in kidney regeneration and disease DOI Creative Commons
Michal Polonsky, Louisa M.S. Gerhardt, Jina Yun

et al.

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

Published: Sept. 5, 2024

Language: Английский

Citations

13
Single-cell sequencing dissects the transcriptional identity of activated fibroblasts and identifies novel persistent distal tubular injury patterns in kidney fibrosis DOI Creative Commons
Valeria Rudman-Melnick, Mike Adam, Kaitlynn Stowers

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 3, 2024

Abstract Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic disease (CKD). Persistent fibroblast activation tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular transcriptional landscapes of specific activated clusters remain elusive. Here, we analyzed single transcriptomic profiles two clinically relevant models which induced robust parenchymal remodeling. We dissected the molecular stroma newly identified three distinctive with “secretory”, “contractile” “vascular” enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline mature markers elevation stromal markers. Notably, frTECs shared identity distal nephron segments embryonic kidney. Moreover, that exhibited previously unrecognized spatial pattern TEC injury, outlined persistent renal including Krt8 Vcam1, while surviving proximal tubules (PTs) showed restored signature. also found long-term a prominent nephrogenic signature, Sox4 Hox gene elevation, prevailed in segments. Our findings might advance intervention fibrotic disease.

Language: Английский

Citations

12
Rodent models of AKI and AKI-CKD transition: an update in 2024 DOI
Ying Fu, Xiang Yu, Qingqing Wei

et al.

AJP Renal Physiology, Journal Year: 2024, Volume and Issue: 326(4), P. F563 - F583

Published: Feb. 1, 2024

Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In past decade, have been developed used to mimic different etiologies acute kidney injury (AKI), AKI chronic disease (CKD) transition or progression, with comorbidities. These applied for both mechanistic preclinical drug development. However, current their limitations, especially since they often do not fully recapitulate pathophysiology human patients, thus need further refinement. Here, we discuss present status these models, including pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, main limitations. Future efforts should focus on establishing robust that simulate major molecular phenotypes its progression.

Language: Английский

Citations

12