From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1755 - 1755

Published: Feb. 1, 2024

This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in transition from acute kidney injury (AKI) disease (AKD) to chronic (CKD). It categorizes biomarkers AKI into stress, damage, functional markers, highlighting their importance early detection, prognosis, clinical applications. review also highlights links between renal pathophysiological mechanisms underlying AKD, including hypoperfusion, sepsis, nephrotoxicity, immune responses. In addition, various molecules play pivotal roles inflammation hypoxia, triggering maladaptive repair, mitochondrial dysfunction, system reactions, cellular senescence cells. Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, Hippo/YAP/TAZ, promote fibrosis impact function. The renin-angiotensin-aldosterone (RAAS) triggers cascade leading fibrosis, with aldosterone exacerbating oxidative stress changes that fibrosis. evidence suggests RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed confirm full impact.

Language: Английский

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Acute kidney injury and maladaptive tubular repair leading to renal fibrosis

Current Opinion in Nephrology & Hypertension, Journal Year: 2020, Volume and Issue: 29(3), P. 310 - 318

Published: March 24, 2020

Purpose of review Despite improvements in acute kidney injury (AKI) detection, therapeutic options to halt the progression AKI chronic disease (CKD) remain limited. In this review, we focus on recent discoveries related pathophysiology CKD continuum, particularly involving renal tubular epithelial cells, and also discuss ongoing clinical trials. While our is injured cells as initiators cascade events resulting paracrine effects other kidney, summation maladaptive responses from various cell types ultimately leads fibrosis dysfunction characteristic CKD. Recent findings that will include, but are not limited to, characterizations of: association between cycle arrest cellular senescence its contribution fibrosis, inflammation with persistent cytokine production lymphocyte infiltration among unrepaired tubules, mitochondrial a unique role cytosolic mitochondria DNA fibrogenesis, prolyl hydroxylase domain proteins potential targets, novel mechanisms Hippo/yes-associated protein/transcriptional coactivator PDZ-binding pathway. Summary Potential address be informed by better understanding fibrogenic pathways. advances suggest additional drug targets pathways leading fibrosis.

Language: Английский

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Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 129(11), P. 4797 - 4816

Published: Oct. 6, 2019

Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance PT DNA damage response (DDR) by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor upstream initiator DDR. In human chronic disease, ATR expression inversely correlates with damage. was upregulated approximately 70% Lotus tetragonolobus lectin-positive (LTL+) cells cisplatin-exposed organoids. Inhibition resulted greater cell injury organoids cultured cells. PT-specific Atr-knockout (ATRRPTC-/-) mice exhibited function impairment, damage, than did WT to induced either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. ATRRPTC-/- had more G2/M phase after similar treatments. conclusion, activation key component DDR, confers protective effect mitigating maladaptive consequent that follow injury.

Language: Английский

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Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy

Nature Reviews Rheumatology, Journal Year: 2020, Volume and Issue: 16(5), P. 255 - 267

Published: March 19, 2020

Language: Английский

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Proximal Tubule Translational Profiling during Kidney Fibrosis Reveals Proinflammatory and Long Noncoding RNA Expression Patterns with Sexual Dimorphism

Journal of the American Society of Nephrology, Journal Year: 2019, Volume and Issue: 31(1), P. 23 - 38

Published: Sept. 19, 2019

Significance Statement Having a comprehensive transcriptional profile of the proximal tubule in health and fibrosis would likely enhance understanding perhaps help explain why CKD progresses more quickly males versus females. To obtain complete picture gene expression tubule, authors performed deep translational profiling this segment mouse model kidney fibrosis. Their findings demonstrate substantial sex differences transcripts expressed cells females, indicate that drives through inflammatory profibrotic paracrine signaling. The study also identified 439 long noncoding RNAs 143 which undergo differential regulation fibrosis, suggesting type RNA has unanticipated regulatory roles Background Proximal injury can initiate CKD, with progression rates are approximately 50% faster precise changes nephron during potential between sexes remain undefined. Methods We generated mice tubule–specific an L10a ribosomal subunit protein fused enhanced green fluorescent protein. unilateral ureteral obstruction surgery on four male three female to induce inflammation collected bulk cortex mRNA at day 5 or 10, sequenced samples depth 30 million reads. applied computational methods identify sex-biased shared molecular responses fibrotic injury, including up- downregulated (lncRNAs) regulators, used situ hybridization validate critical genes pathways. Results >17,000 each group, 145 G-protein–coupled receptors. More than 700 were differentially >4000 displaying altered enriched for proinflammatory Our identification nearly 150 lncRNAs suggests they may have roles. Network analysis prioritized transcription factors such as Irf1 , Nfkb1 Stat3 drivers progression. Conclusions This transcriptomic map revealed sexually dimorphic reflect sex-related disparities modules, previously unappreciated bidirectional lncRNA regulation.

Language: Английский

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Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI

Journal of the American Society of Nephrology, Journal Year: 2021, Volume and Issue: 32(10), P. 2467 - 2483

Published: June 14, 2021

Significance Statement AKI is a frequent clinical problem without definitive therapies. We developed an efficient RNAi therapy against by engineering red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs. REVs targeted Kim-1–binding peptide LTH efficiently delivered P65 Snai1 siRNAs to the injured tubules, leading reduced expression of P-p65 Snai1. Dual suppression inhibited renal inflammation fibrosis in mice subjected ischemia/reperfusion injury unilateral ureteral obstruction, blunted chronic progression ischemic AKI. This study provides platform, REV LTH, for delivery therapeutics into tubular cells, suggests viability as avenue Background significant public health high morbidity mortality. Unfortunately, no treatment available RNA interference (RNAi) new potent method gene tackle this issue. Methods engineered cell–derived treat experimental mouse model after (I/R) obstruction (UUO). Phage display identified that bind kidney molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized transcriptome explore potential targets. Results (REV ) homed accumulated at tubules I/R injury. transcription factors drive Taking advantage established , were consequently blocked tubules. Moreover, dual significantly improved I/R- UUO-induced alleviating tubulointerstitial fibrosis, potently abrogated transition CKD. Conclusions A vesicle platform Kim-1 acutely

Language: Английский

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Autophagy and Renal Fibrosis

Aging and Disease, Journal Year: 2022, Volume and Issue: 13(3), P. 712 - 712

Published: Jan. 1, 2022

Renal fibrosis is a common process of almost all the chronic kidney diseases progressing to end-stage disease. As highly conserved lysosomal protein degradation pathway, autophagy responsible for degrading aggregates, damaged organelles, or invading pathogens maintain intracellular homeostasis. Growing evidence reveals that involved in progression renal fibrosis, both tubulointerstitial compartment and glomeruli. Nevertheless, specific role has still not been fully understood. Therefore, this review we will describe characteristics summarize recent advances understanding functions fibrosis. Moreover, problem existing field possibility as potential therapeutic target have also discussed.

Language: Английский

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Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease

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

Published: Oct. 4, 2022

Abstract Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic disease (CKD). We characterize the distribution tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study functional roles polyploidization using transgenic models drug interventions. identify YAP1-driven TC outside site as a rapid way to sustain residual function early during AKI. This survival mechanism comes at cost senescence polyploid promoting interstitial fibrosis CKD in survivors. However, targeting after phase prevent AKI-CKD transition without influencing lethality. Senolytic treatment prevents blocking repeated cycles. These results revise current pathophysiological concept how responds acute novel druggable target improve prognosis

Language: Английский

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Pathway from Acute Kidney Injury to Chronic Kidney Disease: Molecules Involved in Renal Fibrosis

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 14019 - 14019

Published: Sept. 13, 2023

Acute kidney injury (AKI) is one of the main conditions responsible for chronic disease (CKD), including end-stage renal (ESRD) as a long-term complication. Besides short-term complications, such electrolyte and acid-base disorders, fluid overload, bleeding complications or immune dysfunctions, AKI can develop injuries subsequent CKD through fibrosis pathways. Kidney pathological process defined by excessive extracellular matrix (ECM) deposition, evidenced in with maladaptive architecture restoration. So far, cited processes to transition were epithelial, endothelial, pericyte, macrophage fibroblast myofibroblasts. These are smooth muscle actin (SMA) synthesis abnormal architecture. Recently, progress ESRD gained lot interest, impressive progression discovering mechanisms involved fibrosis, cellular molecular Risk factors mentioned frequency severity injury, diseases uncontrolled hypertension, diabetes mellitus, obesity unmodifiable risk (i.e., genetics, older age gender). To provide better understanding CKD, we have selected relevant updated information regarding AKIs unfavorable evolution incriminated state, along possible therapeutic approaches preventing delaying from AKI.

Language: Английский

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Polyploid tubular cells: a shortcut to stress adaptation

Kidney International, Journal Year: 2024, Volume and Issue: 105(4), P. 709 - 716

Published: Jan. 9, 2024

Tubular epithelial cells (TC) compose the majority of kidney parenchyma and play fundamental roles in maintaining homeostasis. Like other tissues, mostly immature TC with progenitor capabilities are able to replace lost during injury via clonal expansion differentiation. In contrast, differentiated lack this capacity. However, as is frequently exposed toxic injuries, evolution positively selected a response program that endows maintain residual function injury. Recently, we others have described polyploidization TC, mechanism augment remnant after an by rapid hypertrophy. Polyploidy condition characterized more than two complete sets chromosomes. Polyploid often display increased functional capacity generally resilient stress evidenced being conserved across many plants eukaryote species from flies mammals. Here, discuss occurrence polyploidy different contexts conditions how integrates into existing concepts cell responses Collectively, aim at stimulating acquisition novel knowledge field well accelerating translation basic clinical sphere.

Language: Английский

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