EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis DOI Creative Commons

Seung Seob Son,

Hee Seul Jeong, SeongWoo Lee

et al.

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 2, 2024

Abstract Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) a crucial enzyme involved proline-rich protein synthesis, its role remains unclear. The present study revealed that EPRS1 expression levels were increased the fibrotic kidneys of patients mice, especially fibroblasts proximal tubular epithelial cells, on basis single-cell analysis immunostaining kidneys. Moreover, C57BL/6 tm1b heterozygous knockout ( Eprs1 +/− ) pharmacological inhibition with first-in-class inhibitor DWN12088 protected against dysfunction preventing fibroblast activation injury. Interestingly, vitro assays demonstrated EPRS1-mediated nontranslational pathways addition to translational under transforming growth factor β-treated conditions phosphorylating SMAD family member 3 signal transducers activators transcription injured tubules. knockdown catalytic suppressed these pathways, activation, proliferation, subsequent collagen production. Additionally, we caused mitochondrial tubules but this was attenuated inhibition. Our findings suggest ECM accumulation induces via dysfunction. Therefore, targeting could be potential therapeutic target for alleviating injury disease.

Language: Английский

Lymphocytes and innate immune cells in acute kidney injury and repair DOI
Kyungho Lee, Hye Ryoun Jang, Hamid Rabb

et al.

Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: 20(12), P. 789 - 805

Published: Aug. 2, 2024

Language: Английский

Citations

17
Targeting the m6A RNA methyltransferase METTL3 attenuates the development of kidney fibrosis DOI Creative Commons

Hae Rim Jung,

Jeonghwan Lee, Seung-Pyo Hong

et al.

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(2), P. 355 - 369

Published: Feb. 1, 2024

Abstract Kidney fibrosis is a major mechanism underlying chronic kidney disease (CKD). N 6 -methyladenosine (m A) RNA methylation associated with organ fibrosis. We investigated m A profile alterations and the inhibitory effect of in vitro (TGF-β-treated HK-2 cells) vivo (unilateral ureteral obstruction [UUO] mouse model). METTL3-mediated signaling was inhibited using siRNA or METTL3-specific inhibitor STM2457 vitro. In cells, METTL3 protein levels increased dose- time-dependent manner along an increase cellular levels. UUO model, expression were significantly increased. Transcriptomic profiling demonstrated that epithelial-to-mesenchymal transition- inflammation-related pathways methylation. Genetic pharmacologic inhibition cells decreased TGF-β-induced fibrotic marker expression. STM2457-induced attenuated degree vivo. Furthermore, tissues CKD patients diabetic IgA nephropathy. Therefore, targeting could be potential therapeutic strategy for treating

Language: Английский

Citations

15
Recent Update on Acute Kidney Injury-to-Chronic Kidney Disease Transition DOI Creative Commons
Eun Sil Koh, Sungjin Chung

Yonsei Medical Journal, Journal Year: 2024, Volume and Issue: 65(5), P. 247 - 247

Published: Jan. 1, 2024

Acute kidney injury (AKI) is characterized by an abrupt decline of excretory function. The incidence AKI has increased in the past decades. Patients diagnosed with often undergo diverse clinical trajectories, such as early or late recovery, relapses, and even a potential transition from to chronic disease (CKD). Although recent studies have demonstrated strong association between progression CKD, our understanding complex relationship CKD still evolving. No cohort study succeeded painting comprehensive picture these multi-faceted pathways. To address this lack understanding, idea acute (AKD) recently been proposed. This presents new perspective pinpoint period heightened vulnerability following AKI, during which patient could witness substantial glomerular filtration rate, ultimately leading transition. included range conditions collectively known AKD, spanning mild self-limiting severe persistent, AKD can also occur without rapid onset usually seen when dysfunction slowly evolves. In present review, we summarize most findings about explore current state biomarker discovery related discuss latest insights into pathophysiological underpinnings transition, reflect on therapeutic challenges opportunities that lie ahead.

Language: Английский

Citations

8
Unraveling the Multifaceted Roles of Extracellular Vesicles: Insights into Biology, Pharmacology, and Pharmaceutical Applications for Drug Delivery DOI Open Access
Ali Al-Jipouri, Àuria Eritja, Milica Božić

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 485 - 485

Published: Dec. 29, 2023

Extracellular vesicles (EVs) are nanoparticles released from various cell types that have emerged as powerful new therapeutic option for a variety of diseases. EVs involved in the transmission biological signals between cells and regulation processes, highlighting them potential novel targets/platforms therapeutics intervention and/or delivery. Therefore, it is necessary to investigate aspects EVs' biogenesis, biodistribution, metabolism, excretion well safety/compatibility both unmodified engineered upon administration different pharmaceutical dosage forms delivery systems. In this review, we summarize current knowledge essential physiological pathological roles organs organ We provide an overview regarding application targets, therapeutics, drug platforms. also explore approaches implemented over years improve specific EV products routes.

Language: Английский

Citations

11
Silymarin and MSC-exosomes ameliorate thioacetamide-evoked renal fibrosis by inhibiting TGF-β/SMAD pathway in rats DOI Creative Commons

Dina Mohamed Mekawy,

Dina Sabry, Rania Mohamed Sabry

et al.

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: April 18, 2024

Abstract Background TGF-β1 and SMAD3 are particularly pathogenic in the progression of renal fibrosis. Aim This study aimed to evaluate kidney protective potentials silymarin (SM) exosomes mesenchymal stem cells against nephrotoxin thioacetamide (TAA) rats. Methods 32 female rats were randomly assigned into four groups: control group, TAA + SM Exosomes group. The homogenates from all groups examined for expression levels TGF-β receptors I II using real-time PCR, collagen type CTGF proteins ELISA, nuclear SMAD2/3/4, cytoplasmic SMAD2/3, SMAD4 western blot technique. Results Compared injection resulted a significant increase serum urea creatinine, gene TβRI TβRII, protein both proteins, SMAD2/3 complex, SMAD2/3/4 (p-value < 0.0001), with significantly decreased co-SMAD partner, 0.0001). Those effects reversed considerably treatment groups, superiority exosomal regarding SMAD gene, I, returning near-control values > 0.05). Conclusion Using vitro vivo experimental approaches, research discovered reno-protective role BM-MSCs after thioacetamide-induced fibrosis rats, advantage exosomes.

Language: Английский

Citations

4
Double-negative T cells have a reparative role after experimental severe ischemic acute kidney injury DOI
Kyungho Lee,

Sepideh Gharaie,

Johanna T. Kurzhagen

et al.

AJP Renal Physiology, Journal Year: 2024, Volume and Issue: 326(6), P. F942 - F956

Published: April 18, 2024

T cells mediate organ injury and repair. A proportion of unconventional kidney called double-negative (DN) (TCR

Language: Английский

Citations

3
Intermittent Fasting Protects Against the Progression from Acute Kidney Injury to Chronic Kidney Disease DOI Creative Commons
Young Ho Jang, Young-Suk Kim, Seo Rin Kim

et al.

Antioxidants, Journal Year: 2025, Volume and Issue: 14(1), P. 119 - 119

Published: Jan. 20, 2025

Acute kidney injury (AKI) is a major but often underestimated risk factor for the development of chronic disease (CKD). Exploring innovative approaches to prevent this progression critical. Intermittent fasting (IF), recognized its metabolic and anti-inflammatory benefits, may offer protective effects in context. Using unilateral ischemia-reperfusion (UIRI) model male C57BL/6 mice, we evaluated impact IF on tubulointerstitial fibrosis tubular epithelial–mesenchymal transition (EMT) over 8 weeks. Mice group followed 5:2 regimen, 24 h twice weekly. Four groups were studied: control, IF, UIRI, + UIRI. The UIRI exhibited increased EMT, both which significantly attenuated group. also reduced levels TGF-β1, phosphorylated NF-κB p65, inflammatory cytokines, F4/80-positive macrophages, along with markers oxidative stress. These findings highlight IF’s ability mitigate EMT through reductions inflammation stress during AKI-to-CKD progression. Our study suggests that serve as promising dietary strategy AKI from advancing into CKD.

Language: Английский

Citations

0
Single-cell lineage tracing approaches to track kidney cell development and maintenance DOI

Baul Yoon,

Hayoung Kim,

Su Woong Jung

et al.

Kidney International, Journal Year: 2024, Volume and Issue: 105(6), P. 1186 - 1199

Published: March 28, 2024

Language: Английский

Citations

3
The role of protein prenylation inhibition through targeting FPPS by zoledronic acid in the prevention of renal fibrosis in rats DOI Creative Commons
Reham Hussein Mohamed, Dina Sayed Abdelrahim,

Nesma Hussein Abdel hay

et al.

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

Published: Aug. 7, 2024

Abstract Renal fibrosis (RF) represents the most widespread pathological condition in chronic kidney disease (CKD). Recently, protein prenylation has been implicated fibrosis’s progression. The research examined renoprotective effect of zoledronic acid (ZA) (50 µg/kg/week) a rat model carbon tetrachloride (CCl 4 )-induced RF through targeting prenylation. Forty Wistar male rats were split up into control group, vehicle-treated model-RF and RF-ZA group. Mean arterial blood pressure (MBP), BUN, serum creatinine, urine albumin–creatinine ratio (uACR), levels farnesyl pyrophosphate (FPP), tumour necrosis factor-alpha (TNF-α), transforming growth factor-β (TGF-β), malondialdehyde (MDA), catalase gene expression synthase (FPPS) nuclear factor-kB (NF-κB) measured. Immunohistochemical staining for renal interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), caspase-3, as well histopathological alterations, assessed. ZA considerably ceased reduction MBP, markedly reduced uACR, FPPS, FPP, NF-κB, TGF-β, TNF-α, MDA, significantly increased compared to rats. ameliorated CCl -induced alterations suppressed α-SMA, IL-6. In conclusion, preserved function prevented model. These achieved mainly by inhibiting FPPS.

Language: Английский

Citations

1
Cell and rat serum, urine and tissue metabolomics analysis elucidates the key pathway changes associated with chronic nephropathy and reveals the mechanism of action of rhein DOI Creative Commons
Li Wang, Xixi Yu,

Hongju Li

et al.

Chinese Medicine, Journal Year: 2023, Volume and Issue: 18(1)

Published: Dec. 1, 2023

Rhein can significantly delay the progression of chronic nephropathy. However, its mechanism action has not been adequately elaborated, which hinders extensive clinical application. In this work, effects rhein on models TGF-β-induced NRK-49F cellular fibrosis and rat renal ischemia-reperfusion were evaluated using metabolomics western blotting.The metabolic profiles cells urine, serum, kidney tissues in control, model, groups investigated UPLC-QTOF-MS. The levels p-P65, p-IKK, p-AKT, p-P38, p-JNK AP-1 measured blotting immunofluorescence methods. Molecular docking network pharmacology methods employed to explore relationship between potential targets key proteins NF-κB MAPK signaling pathways.Various metabolites, including sphingolipids, ceramides, phosphatidylcholine, lysophosphatidylcholine,14-hydroxy-E4-neuroprostane E, 5-HPETE, present cell, tissue, serum samples; however, few metabolites matches exactly among four type biological samples. These differential effectively differentiated groups. Pathway enrichment analysis unveiled that sphingolipid metabolism, arachidonic acid glycerophospholipid metabolism closely related Phosphorylation AKT, IKK, P65 was reduced by treatment. Network molecular showed might regulated expression AKT pathways.In brief, delays nephropathy via pathways, MAPKs provides foundation for development

Language: Английский

Citations

3