Targeting the progression of chronic kidney disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(5), P. 269 - 288

Published: Feb. 14, 2020

Language: Английский

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Autophagy in kidney homeostasis and disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(9), P. 489 - 508

Published: July 23, 2020

Language: Английский

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Kidney fibrosis: from mechanisms to therapeutic medicines

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 17, 2023

Abstract Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading scarring, a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. fibrosis identified tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, vascular rarefaction. Fibrotic niche, where organ initiates, complex interplay between injured parenchyma (like tubular cells) multiple non-parenchymal cell lineages (immune mesenchymal located spatially within scarring areas. Although the mechanisms are complicated due kinds cells involved, with help single-cell technology, many key questions have been explored, such as what kind renal tubules profibrotic, myofibroblasts originate, which immune how communicate each other. In addition, genetics epigenetics deeper that regulate fibrosis. And reversible nature epigenetic changes including DNA methylation, RNA interference, chromatin remodeling, gives an opportunity stop or reverse therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) developed delay progression recent years. Furthermore, better understanding also favored discover biomarkers fibrotic injury. review, we update advances mechanism summarize novel treatment for CKD.

Language: Английский

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The fibrogenic niche in kidney fibrosis: components and mechanisms

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 18(9), P. 545 - 557

Published: July 4, 2022

Language: Английский

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KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(5), P. 1042 - 1061.e7

Published: May 1, 2021

Language: Английский

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Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(2)

Published: Feb. 15, 2021

Abstract Chemotherapy drug-induced nephrotoxicity limits clinical applications for treating cancers. Pyroptosis, a newly discovered programmed cell death, was recently reported to be associated with kidney diseases. However, the role of pyroptosis in chemotherapeutic has not been fully clarified. Herein, we demonstrate that drug cisplatin or doxorubicin, induces cleavage gasdermin E (GSDME) cultured human renal tubular epithelial cells, time- and concentration-dependent manner. Morphologically, cisplatin- doxorubicin-treated cells exhibit large bubbles emerging from membrane. Furthermore, activation caspase 3, 9, is GSDME cells. Meanwhile, silencing alleviates doxorubicin-induced HK-2 by increasing viability decreasing LDH release. In addition, treatment Ac-DMLD-CMK, polypeptide targeting mouse 3-Gsdme signaling, inhibits 3 Gsdme activation, deterioration function, attenuates injury, reduces inflammatory cytokine secretion vivo. Specifically, depends on ERK JNK signaling. NAC, reactive oxygen species (ROS) inhibitor, through signaling Thus, speculate induced chemotherapy drugs mediated ROS-JNK-caspase 3-GSDME implying therapies may prove efficacious overcoming nephrotoxicity.

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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Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis

Autophagy, Journal Year: 2022, Volume and Issue: 19(1), P. 256 - 277

Published: May 1, 2022

Following acute kidney injury (AKI), renal tubular cells may stimulate fibroblasts in a paracrine fashion leading to interstitial fibrosis, but the factors and their regulation under this condition remain elusive. Here we identify macroautophagy/autophagy-dependent FGF2 (fibroblast growth factor 2) production cells. Upon induction, acts as key activate for fibrosis. After ischemic AKI mice, autophagy activation persisted weeks In inducible, tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7-KO) deficiency induced after suppressed pro-fibrotic phenotype reduced Among major cytokines, iRT-atg7-KO mice specifically diminished FGF2. Autophagy inhibition also attenuated expression TGFB1/TGF-β1 (transforming factor, beta 1)-treated Consistent with action, culture medium of TGFB1-treated stimulated fibroblasts, effect was by neutralizing antibody fgf2- or atg7-deletion human, compared non-AKI, biopsies from post-AKI patients had higher levels cells, which showed significant correlations These results indicate that persistent induces transformation secretion FGF2, activates fibrosis during maladaptive repair.Abbreviations: 3-MA: 3-methyladnine; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/β-actin: actin, beta; AKI: injury; ATG/Atg: related; BUN: blood urea nitrogen; CCN2/CTGF: cellular communication network 2; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CKD: chronic disease; CM: conditioned medium; COL1A1: collagen, type I, 1; COL4A1: IV, CQ: chloroquine; ECM: extracellular matrix; eGFR: estimated glomerular filtration rate; ELISA: enzyme-linked immunosorbent assay; FGF2: fibroblast FN1: fibronectin FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAVCR1/KIM-1: hepatitis A virus receptor IHC: immunohistochemistry; IRI: ischemia-reperfusion ISH: situ hybridization; LTL: lotus tetragonolobus lectin; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 MTOR: mechanistic target rapamycin kinase; PDGFB: platelet derived B polypeptide; PPIB/cyclophilin B: peptidylprolyl isomerase B; RT-qPCR: real time-quantitative PCR; SA-GLB1/β-gal: senescence-associated galactosidase, SASP: secretory phenotype; sCr: serum creatinine; SQSTM1/p62: sequestosome TASCC: TOR-autophagy spatial coupling compartment; TGFB1/TGF-β1: transforming VIM: vimentin.

Language: Английский

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Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

eLife, Journal Year: 2021, Volume and Issue: 10

Published: July 19, 2021

Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair mice humans. Using single-cell transcriptomic mouse genetic approaches, we show proximal tubular (PT) cells develop molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT transiently appear after mild injury return to their original without inducing fibrosis, severe they accumulate contribute persistent inflammation. This transient significantly downregulates glutathione metabolism genes, making the vulnerable stress. Genetic induction high leads accumulation cells, enhancing inflammation fibrosis. Our study broadens roles from being trigger include promotion proinflammatory underlie repair.

Language: Английский

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Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges

Annals of Intensive Care, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 2, 2022

Abstract Background Post‐intensive care syndrome (PICS) encompasses physical, cognition, and mental impairments persisting after intensive unit (ICU) discharge. Ultimately it significantly impacts the long‐term prognosis, both in functional outcomes survival. Thus, survivors often develop permanent disabilities, consume a lot of healthcare resources, may experience prolonged suffering. This review aims to present multiple facets PICS, decipher its underlying mechanisms, highlight future research directions. Main text abridges translational data chronic critical illness (CCI) PICS. We focus first on ICU-acquired weakness, characterized by impaired contractility, muscle wasting, atrophy during recovery phase, which involves anabolic resistance, capacity regeneration, mitochondrial dysfunction, abnormalities calcium homeostasis. Second, we discuss clinical relevance post-ICU cognitive impairment neuropsychological disability, association with delirium ICU stay, putative role low-grade long-lasting inflammation. Third, describe profound persistent qualitative quantitative alteration innate adaptive response. Fourth, biological mechanisms progression from acute kidney injury, opening field for renoprotective strategies. Fifth, report pulmonary consequences ARDS mechanical ventilation. Finally, several specificities children, including influence child’s pre-ICU condition, development, maturation. Conclusions Recent understandings substratum PICS’ distinct features need rethink our patient trajectories long term. A better knowledge this precipitating factors is necessary protocols strategies alleviate CCI PICS ultimately improve recovery.

Language: Английский

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