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

Molecular pathways that drive diabetic kidney disease DOI Creative Commons

Samer Mohandes,

Tomohito Doke, Hailong Hu

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(4)

Published: Feb. 14, 2023

Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney (DKD) responsible for close to half all chronic cases. DKD usually develops in genetically susceptible individual as result poor metabolic (glycemic) control. Molecular genetic studies indicate the key role podocytes endothelial cells driving albuminuria early diabetes. Proximal tubule changes show strong association glomerular filtration rate. Hyperglycemia represents cellular stress by altering metabolism imposing an excess workload requiring energy oxygen proximal cells. Changes induce adaptive hypertrophy reorganization actin cytoskeleton. Later, mitochondrial defects contribute increased oxidative activation inflammatory pathways, causing progressive function decline fibrosis. Blockade renin-angiotensin system or sodium-glucose cotransporter associated protection slowing decline. Newly identified molecular pathways could provide basis development much-needed novel therapeutics.

Language: Английский

Citations

185
Regulated cell death pathways in kidney disease DOI Open Access
Ana B. Sanz, María Dolores Sánchez-Niño, Adrián M. Ramos

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(5), P. 281 - 299

Published: March 23, 2023

Language: Английский

Citations

166
Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration DOI Creative Commons
Michael S. Balzer, Tomohito Doke, Ya‐Wen Yang

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 11, 2022

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic are poorly understood. We developed a model of regeneration by titrating ischemic injury dose. performed detailed biochemical histological analysis profiled transcriptomic changes at bulk single-cell level (> 110,000 cells) over time. Our highlights proximal tubule cells as key susceptible injury. Adaptive correlated with fatty acid oxidation oxidative phosphorylation. identify specific maladaptive/profibrotic cluster long ischemia, which expresses proinflammatory profibrotic cytokines myeloid cell chemotactic factors. Druggability pyroptosis/ferroptosis vulnerable in these cells. Pharmacological targeting vivo pushed towards ameliorates fibrosis. In summary, our defines differences identifies druggable for pharmacological intervention prevent

Language: Английский

Citations

124
Gasdermins and pyroptosis in the kidney DOI

Esteban Elias,

Brayden Lyons,

Daniel A. Muruve

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(5), P. 337 - 350

Published: Jan. 3, 2023

Language: Английский

Citations

118
Lineage Tracing and Single-Nucleus Multiomics Reveal Novel Features of Adaptive and Maladaptive Repair after Acute Kidney Injury DOI
Louisa M.S. Gerhardt,

Kari Koppitch,

Jordi van Gestel

et al.

Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 34(4), P. 554 - 571

Published: Jan. 13, 2023

Significance Statement Understanding the mechanisms underlying adaptive and maladaptive renal repair after AKI their long-term consequences is critical to kidney health. The authors used lineage tracing of cycling cells single-nucleus multiomics (profiling transcriptome chromatin accessibility) AKI. They demonstrated that triggers a cell-cycle response in most epithelial nonepithelial cell types. also showed proinflammatory proximal tubule (PTCs) persist until 6 months post-AKI, although they decreased abundance over time, part, through death. Single-nucleus lineage-traced revealed regulatory features repair. These included activation state–specific transcription factors cis-regulatory elements, effects PTCs even repair, weeks injury event. Background proliferative as part an intrinsic cellular program, which can lead restoring structure function, or with persistence injured altered structure. However, molecular understanding these programs limited. Methods To examine transcriptional responses same upon ischemia-reperfusion (IRI), we combined genetic fate mapping ( Ki67 + ) labeled early IRI multiomics—profiling accessibility nucleus—and generated dataset 83,315 nuclei. Results triggered broad cycle preceded by type–specific global changes nephron, collecting vascular systems, stromal immune We observed heterogeneous population throughout segments marked loss from 4 months. Gene expression profiling nuclei highlighted differences between activity elements factors, accompanied corresponding target gene expression. Adaptive was associated reduced genes encoding transmembrane transport proteins essential function. Conclusions Analysis genome organization single-cell resolution using offers new insight into regulation Weeks mild-to-moderate IRI, aberrant epigenetic landscape, exhibit profile following

Language: Английский

Citations

63
Role of necroptosis in kidney health and disease DOI
Benedikt Kolbrink, Friedrich Alexander von Samson‐Himmelstjerna, James M. Murphy

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(5), P. 300 - 314

Published: Jan. 3, 2023

Language: Английский

Citations

49
Diabetes mellitus—Progress and opportunities in the evolving epidemic DOI
E. Dale Abel, Anna L. Gloyn, Carmella Evans‐Molina

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(15), P. 3789 - 3820

Published: July 1, 2024

Language: Английский

Citations

48
Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence DOI Creative Commons
Lingzhi Li, Ting Xiang, Jingjing Guo

et al.

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

Published: April 13, 2024

Abstract Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells abnormally elevated fibrotic kidneys. By screening these crotonylated/acetylated factors, crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) found to remarkably increase 3 9 (H3K9cr) level without influencing H3K9ac kidneys and cells. The integrated analysis ChIP-seq RNA-seq reveal the hub proinflammatory cytokine IL-1β, which regulated by H3K9cr, play crucial fibrogenesis. Furthermore, genetic pharmacologic inhibition both suppress H3K9cr-mediated IL-1β expression, thereby alleviate IL-1β-dependent macrophage activation cell senescence delay renal Collectively, our findings uncover H3K9cr exerts critical, previously unrecognized role fibrosis, where represents an attractive drug target slow disease progression.

Language: Английский

Citations

30
Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression DOI
Amin Abedini, Jonathan Levinsohn, Konstantin A. Klötzer

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(8), P. 1712 - 1724

Published: July 24, 2024

Language: Английский

Citations

28
The key role of altered tubule cell lipid metabolism in kidney disease development DOI Creative Commons
Lauren E. Lee, Tomohito Doke, Dhanunjay Mukhi

et al.

Kidney International, Journal Year: 2024, Volume and Issue: 106(1), P. 24 - 34

Published: April 16, 2024

Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism observed patients with kidney disease. Defects oxidation and increased uptake, especially the context of hyperlipidemia proteinuria, contribute to this excess build-up exacerbate disease development. Recent studies also highlighted role de novo lipogenesis fibrosis. The defect causes starvation. Increased synthesis, lower can cause toxic build-up, reactive oxygen species generation, mitochondrial damage. A better understanding these metabolic processes may open new treatment avenues for diseases targeting metabolism.

Language: Английский

Citations

24