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Rationale: Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown. Methods: Isg15 knockout (Isg15 KO) mice challenged with bilateral or unilateral IRI, cisplatin, or UUO were used to investigate its role in AKI. We established cellular models with overexpression or knockout of ISG15 and subjected them to hypoxia-reoxygenation, cisplatin, or transforming growth factor- ß1 (TGF-ß1) stimulation. Renal RNA-seq data obtained from AKI models sourced from public databases and our studies, were utilized to examine the expression profiles of ISG15 and its associated genes. Additionally, published single cell RNA-seq data from human kidney allograft biopsies and mouse IRI model were analyzed to investigate the expression patterns of ISG15 and the type I TGF-ß receptor (TGFßR1). Western blotting, qPCR, co-immunoprecipitation, and immunohistochemical staining assays were performed to validate our findings. Results: Alleviated pathological injury and renal function were observed in Isg15 KO mice with IRI-, cisplatin-, or UUO-induced AKI and the following AKI-to-CKD transition. In hypoxia-reoxygenation, cisplatin or TGF-ß1 treated HK-2 cells, knockout ISG15 reduced stimulus-induced cell fibrosis, while overexpression of ISG15 with modification capacity exacerbated cell fibrosis. Immunoprecipitation assays demonstrated that ISG15 promoted ISGylation of TGFßR1, and inhibited its ubiquitination. Moreover, knockout of TGFßR1 blocked ISG15's fibrosis-exacerbating effect in HK-2 cells, while overexpression of TGFßR1 abolished the renal protective effect of ISG15 knockout during IRI-induced kidney injury. Conclusions: ISG15 plays an important role in the development of AKI and subsequent AKI-to-CKD transition by promoting TGFßR1 ISGylation.
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Lesión Renal Aguda , Cisplatino , Citocinas , Ratones Noqueados , Daño por Reperfusión , Ubiquitinas , Animales , Humanos , Masculino , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Cisplatino/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Riñón/metabolismo , Riñón/patología , Ratones Endogámicos C57BL , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Ubiquitinas/metabolismo , Ubiquitinas/genética , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/genéticaRESUMEN
Renal fibrosis, a critical factor in the development of chronic kidney disease (CKD), is predominantly initiated by acute kidney injury (AKI) and subsequent maladaptive repair resulting from pharmacological or pathological stimuli. Phosphatase and tensin homolog (PTEN), also known as phosphatase and tensin-associated phosphatase, plays a pivotal role in regulating the physiological behavior of renal tubular epithelial cells, glomeruli, and renal interstitial cells, thereby preserving the homeostasis of renal structure and function. It significantly impacts cell proliferation, apoptosis, fibrosis, and mitochondrial energy metabolism during AKI-to-CKD transition. Despite gradual elucidation of PTEN's involvement in various kidney injuries, its specific role in AKI and maladaptive repair after injury remains unclear. This review endeavors to delineate the multifaceted role of PTEN in renal pathology during AKI and CKD progression along with its underlying mechanisms, emphasizing its influence on oxidative stress, autophagy, non-coding RNA-mediated recruitment and activation of immune cells as well as renal fibrosis. Furthermore, we summarize prospective therapeutic targeting strategies for AKI and CKD-treatment related diseases through modulation of PTEN.
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Acute kidney injury (AKI), characterized by a sudden decline in kidney function involving tubular damage and epithelial cell death, can lead to progressive tissue fibrosis and chronic kidney disease due to interstitial fibroblast activation and tissue repair failures that lack direct treatments. After an AKI episode, surviving renal tubular cells undergo cycles of dedifferentiation, proliferation and redifferentiation while fibroblast activity increases and then declines to avoid an exaggerated extracellular matrix deposition. Appropriate tissue recovery versus pathogenic fibrotic progression depends on fine-tuning all these processes. Identifying endogenous factors able to affect any of them may offer new therapeutic opportunities to improve AKI outcomes. Galectin-8 (Gal-8) is an endogenous carbohydrate-binding protein that is secreted through an unconventional mechanism, binds to glycosylated proteins at the cell surface and modifies various cellular activities, including cell proliferation and survival against stress conditions. Here, using a mouse model of AKI induced by folic acid, we show that pre-treatment with Gal-8 protects against cell death, promotes epithelial cell redifferentiation and improves renal function. In addition, Gal-8 decreases fibroblast activation, resulting in less expression of fibrotic genes. Gal-8 added after AKI induction is also effective in maintaining renal function against damage, improving epithelial cell survival. The ability to protect kidneys from injury during both pre- and post-treatments, coupled with its anti-fibrotic effect, highlights Gal-8 as an endogenous factor to be considered in therapeutic strategies aimed at improving renal function and mitigating chronic pathogenic progression.
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Lesión Renal Aguda , Fibrosis , Ácido Fólico , Galectinas , Animales , Masculino , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Ácido Fólico/farmacología , Galectinas/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones Endogámicos C57BLRESUMEN
Background: Surgical aortic valve replacement (SAVR) is often complicated by acute kidney injury (AKI). Identifying patients at risk of AKI is important to start nephroprotective strategies or renal replacement therapy (RRT). This study investigated the incidence and risk factors of post-operative AKI in SAVR patients. Chronic kidney disease (CKD) developed in the post-cardiac-surgery follow-up period was also assessed. Methods: A total of 462 SAVR patients were retrospectively enrolled. The primary endpoint was the occurrence rate of AKI after surgery. Kidney recovery, during two planned outpatient clinic nephrological visits within 12 months after the surgery, was assessed. Results: A total of 76 patients experienced an AKI event. A Kaplan-Meier analysis revealed that subjects with CKD stage IV had a time to progression of 2.7 days, compared to patients with stages I-II, who were characterized by the slowest progression time, >11.2 days. A Cox regression indicated that CKD stages predicted a higher risk of AKI independently of other variables. During their ICU stay, 23 patients died, representing 5% of the population, most of them requiring RRT during their ICU stay. A severe CKD before the surgery was closely related to perioperative mortality. During the follow-up period, 21 patients with AKI worsened their CKD stage. Conclusions: AKI represents a common complication for SAVR patients in the early post-operative period, prolonging their ICU stay, with negative effects on survival, especially if RRT was required. Pre-operative CKD >3 stage is an independent risk factor for AKI in patients undergoing SAVR.
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BACKGROUND: Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. METHODS: SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. RESULTS: Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. CONCLUSIONS: Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.
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Intestinal microbiota and their metabolites affect systemic inflammation and kidney disease outcomes. Here, we investigated the key metabolites associated with the acute kidney injury (AKI)-to chronic kidney disease (CKD) transition and the effect of antibiotic-induced microbiota depletion (AIMD) on this transition. In 61 patients with AKI, 59 plasma metabolites were assessed to determine the risk of AKI-to-CKD transition. An AKI-to-CKD transition murine model was established four weeks after unilateral ischemia-reperfusion injury (IRI) to determine the effects of AIMD on the gut microbiome, metabolites, and pathological responses related to CKD transition. Human proximal tubular epithelial cells were challenged with CKD transition-related metabolites, and inhibitory effects of NADPH oxidase 2 (NOX2) signals were tested. Based on clinical metabolomics, plasma trimethylamine N-oxide (TMAO) was associated with a significantly increased risk for AKI-to-CKD transition [adjusted odds ratio 4.389 (95% confidence interval 1.106-17.416)]. In vivo, AIMD inhibited a unilateral IRI-induced increase in TMAO, along with a decrease in apoptosis, inflammation, and fibrosis. The expression of NOX2 and oxidative stress decreased after AIMD. In vitro, TMAO induced fibrosis with NOX2 activation and oxidative stress. NOX2 inhibition successfully attenuated apoptosis, inflammation, and fibrosis with suppression of G2/M arrest. NOX2 inhibition (in vivo) showed improvement in pathological changes with a decrease in oxidative stress without changes in TMAO levels. Thus, TMAO is a key metabolite associated with the AKI-to-CKD transition, and NOX2 activation was identified as a key regulator of TMAO-related AKI-to-CKD transition both in vivo and in vitro.
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Lesión Renal Aguda , Antibacterianos , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Metilaminas , NADPH Oxidasa 2 , Estrés Oxidativo , Insuficiencia Renal Crónica , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/microbiología , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Metilaminas/sangre , Metilaminas/metabolismo , Animales , NADPH Oxidasa 2/antagonistas & inhibidores , NADPH Oxidasa 2/metabolismo , Humanos , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/complicaciones , Persona de Mediana Edad , Ratones , Estrés Oxidativo/efectos de los fármacos , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Ratones Endogámicos C57BL , Femenino , Daño por Reperfusión/prevención & control , Anciano , Apoptosis/efectos de los fármacos , Progresión de la EnfermedadRESUMEN
Hypoxia is the key pathobiological trigger of tubular oxidative stress and cell death that drives the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). The mitochondrial-rich proximal tubular epithelial cells (PTEC) are uniquely sensitive to hypoxia and thus, are pivotal in propagating the sustained tubular loss of AKI-to-CKD transition. Here, we examined the role of PTEC-derived small extracellular vesicles (sEV) in propagating the 'wave of tubular death'. Ex vivo patient-derived PTEC were cultured under normoxia (21 % O2) and hypoxia (1 % O2) on Transwell inserts for isolation and analysis of sEV secreted from apical versus basolateral PTEC surfaces. Increased numbers of sEV were secreted from the apical surface of hypoxic PTEC compared with normoxic PTEC. No differences in basolateral sEV numbers were observed between culture conditions. Biological pathway analysis of hypoxic-apical sEV cargo identified distinct miRNAs linked with cellular injury pathways. In functional assays, hypoxic-apical sEV selectively induced ferroptotic cell death (↓glutathione peroxidase-4, ↑lipid peroxidation) in autologous PTEC compared with normoxic-apical sEV. The addition of ferroptosis inhibitors, ferrostatin-1 and baicalein, attenuated PTEC ferroptosis. RNAse A pretreatment of hypoxic-apical sEV also abrogated PTEC ferroptosis, demonstrating a role for sEV RNA in ferroptotic 'wave of death' signalling. In line with these in vitro findings, in situ immunolabelling of diagnostic kidney biopsies from AKI patients with clinical progression to CKD (AKI-to-CKD transition) showed evidence of ferroptosis propagation (increased numbers of ACSL4+ PTEC), while urine-derived sEV (usEV) from these 'AKI-to-CKD transition' patients triggered PTEC ferroptosis (↑lipid peroxidation) in functional studies. Our data establish PTEC-derived apical sEV and their intravesicular RNA as mediators of tubular lipid peroxidation and ferroptosis in hypoxic kidney injury. This concept of how tubular pathology is propagated from the initiating insult into a 'wave of death' provides novel therapeutic check-points for targeting AKI-to-CKD transition.
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Lesión Renal Aguda , Ferroptosis , Insuficiencia Renal Crónica , Humanos , Túbulos Renales Proximales , Riñón/metabolismo , Células Epiteliales/metabolismo , Hipoxia/metabolismo , Lesión Renal Aguda/metabolismo , Insuficiencia Renal Crónica/metabolismo , ARNRESUMEN
Acute kidney injury (AKI) affects about half of patients admitted to the intensive care unit (ICU), and worsens their short- and long-term outcomes. Apparently self-limiting AKI episodes initiate a progression toward chronic kidney disease (CKD) through cellular and molecular mechanisms that are yet to be explained. In particular, persistent AKI, defined in 2016 by the Acute Dialysis Quality Initiative as an AKI which lasts more than 48 h from its onset, has been correlated with higher morbidity and mortality, and with a higher progression to acute kidney disease (AKD) and CKD than transient AKI (i.e. AKI with a reversal within 48 h). This classification has been also used in the setting of solid organ transplantation, demonstrating similar outcomes. Due to its incidence and poor prognosis and because prompt interventions seem to change its course, persistent AKI should be recognized early and followed-up also after its recovery. However, while AKI and CKD are well-described syndromes, persistent AKI and AKD are relatively new entities. The purpose of this review is to highlight the key phases of persistent AKI in ICU patients in terms of both clinical and mechanistic features in order to offer to clinicians and researchers an updated basis from which to start improving patients' care and direct future research.
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After acute kidney injury (AKI), renal function continues to deteriorate in some patients. In a pro-inflammatory and profibrotic environment, the proximal tubules are subject to maladaptive repair. In the AKI-to-CKD transition, impaired recovery from AKI reduces tubular and glomerular filtration and leads to chronic kidney disease (CKD). Reduced kidney secretion capacity is characterized by the plasma accumulation of biologically active molecules, referred to as uremic toxins (UTs). These toxins have a role in the development of neurological, cardiovascular, bone, and renal complications of CKD. However, UTs might also cause CKD as well as be the consequence. Recent studies have shown that these molecules accumulate early in AKI and contribute to the establishment of this pro-inflammatory and profibrotic environment in the kidney. The objective of the present work was to review the mechanisms of UT toxicity that potentially contribute to the AKI-to-CKD transition in each renal compartment.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Toxinas Biológicas , Humanos , Tóxinas Urémicas , Insuficiencia Renal Crónica/complicaciones , RiñónRESUMEN
High-mobility group protein box 1 (HMGB1) is a member of a highly conserved high-mobility group protein present in all cell types. HMGB1 plays multiple roles both inside and outside the cell, depending on its subcellular localization, context, and post-translational modifications. HMGB1 is also associated with the progression of various diseases. Particularly, HMGB1 plays a critical role in CKD progression and prognosis. HMGB1 participates in multiple key events in CKD progression by activating downstream signals, including renal inflammation, the onset of persistent fibrosis, renal aging, AKI-to-CKD transition, and important cardiovascular complications. More importantly, HMGB1 plays a distinct role in the chronic pathophysiology of kidney disease, which differs from that in acute lesions. This review describes the regulatory role of HMGB1 in renal homeostasis and summarizes how HMGB1 affects CKD progression and prognosis. Finally, some promising therapeutic strategies for the targeted inhibition of HMGB1 in improving CKD are summarized. Although the application of HMGB1 as a therapeutic target in CKD faces some challenges, a more in-depth understanding of the intracellular and extracellular regulatory mechanisms of HMGB1 that underly the occurrence and progression of CKD might render HMGB1 an attractive therapeutic target for CKD.
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Lesión Renal Aguda , Proteína HMGB1 , Insuficiencia Renal Crónica , Humanos , Proteína HMGB1/metabolismo , Lesión Renal Aguda/epidemiología , Insuficiencia Renal Crónica/tratamiento farmacológico , Riñón/metabolismo , Envejecimiento , Progresión de la EnfermedadRESUMEN
Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes that represent a global public health challenge. Here, we identified a specific role of survival of motor neuron (SMN) in ischemia/reperfusion (I/R)-induced kidney injury and progression of CKD. SMN was an essential protein in all cell type and was reported to play important roles in multiple fundamental cellular homeostatic pathways. However, the function of SMN in experimental models of I/R-induced kidney fibrosis has not extensively studied. Genetic ablation of SMN or small interfering RNA-base knockdown of SMN expression aggravated the tubular injury and interstitial fibrosis. Administration of scAAV9-CB-SMN or epithelial cell overexpression of SMN reduced I/R-induced kidney dysfunction and attenuated AKI-to-CKD transition, indicating that SMN is vital for the preservation and recovery of tubular phenotype. Our data showed that the endoplasmic reticulum stress (ERS) induced by I/R was persistent and became progressively more severe in the kidney without SMN. On the contrary, overexpression of SMN prevented against I/R-induced ERS and tubular cell damage. In summary, our data collectively substantiate a critical role of SMN in regulating the ERS activation and phenotype of AKI-to-CKD transition that may contribute to renal pathology during injury and repair.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Proteína 1 para la Supervivencia de la Neurona Motora , Humanos , Lesión Renal Aguda/genética , Estrés del Retículo Endoplásmico/genética , Fibrosis , Haploinsuficiencia , Isquemia , Riñón , Insuficiencia Renal Crónica/genética , Daño por Reperfusión/genética , Proteína 1 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.
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Acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition is a slow but persistent progression toward end-stage kidney disease. Earlier reports have shown that Hippo components, such as Yes-associated protein (YAP) and its homolog Transcriptional coactivator with PDZ-binding motif (TAZ), regulate inflammation and fibrogenesis during the AKI-to-CKD transition. Notably, the roles and mechanisms of Hippo components vary during AKI, AKI-to-CKD transition, and CKD. Hence, it is important to understand these roles in detail. This review addresses the potential of Hippo regulators or components as future therapeutic targets for halting the AKI-to-CKD transition.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Humanos , Vía de Señalización Hippo , Transducción de Señal/fisiología , Factores de Transcripción/metabolismoRESUMEN
Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute, chronic, and asymptomatic leptospiral infections are closely linked to acute and chronic kidney disease (CKD) and renal fibrosis. Leptospires affect renal function by infiltrating kidney cells via the renal tubules and interstitium and surviving in the kidney by circumventing the immune system. The most well-known pathogenic molecular mechanism of renal tubular damage caused by leptospiral infection is the direct binding of the bacterial outer membrane protein LipL32 to toll-like receptor-2 expressed in renal tubular epithelial cells (TECs) to induce intracellular inflammatory signaling pathways. These pathways include the production of tumor necrosis factor (TNF)-α and nuclear factor kappa activation, resulting in acute and chronic leptospirosis-related kidney injury. Few studies have investigated the relationship between acute and chronic renal diseases and leptospirosis and further evidence is necessary. In this review, we intend to discuss the roles of acute kidney injury (AKI) to/on CKD in leptospirosis. This study reviews the molecular pathways underlying the pathogenesis of leptospirosis kidney disease, which will assist in concentrating on potential future research directions.
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Lesión Renal Aguda , Leptospira , Leptospirosis , Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/patología , Riñón/microbiología , Riñón/patología , Leptospira/metabolismoRESUMEN
Uromodulin is recognized as a protective factor during AKI-to-CKD progression, but the mechanism remains unclear. We previously reported that uromodulin interacts with complement factor H (CFH) in vitro, and currently aimed to study the expression and interaction evolution of uromodulin and CFH during AKI-to-CKD transition. We successfully established a rat model of AKI-to-CKD transition induced by a four-time cisplatin treatment. The blood levels of BUN, SCR, KIM-1 and NGAL increased significantly during the acute injury phase and exhibited an uptrend in chronic progression. PAS staining showed the nephrotoxic effects of four-time cisplatin injection on renal tubules, and Sirius red highlighted the increasing collagen fiber. Protein and mRNA levels of uromodulin decreased while urine levels increased in acute renal injury on chronic background. An extremely diminished level of uromodulin correlated with severe renal fibrosis. RNA sequencing revealed an upregulation of the alternative pathway in the acute stage. Renal CFH gene expression showed an upward tendency, while blood CFH localized less, decreasing the abundance of CFH in kidney and following sustained C3 deposition. A co-IP assay detected the linkage between uromodulin and CFH. In the model of AKI-to-CKD transition, the levels of uromodulin and CFH decreased, which correlated with kidney dysfunction and fibrosis. The interaction between uromodulin and CFH might participate in AKI-to-CKD transition.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Ratas , Animales , Cisplatino/efectos adversos , Uromodulina/genética , Factor H de Complemento/genética , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Riñón/patología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , FibrosisRESUMEN
BACKGROUND: Thromboembolic events are prevalent in chronic kidney disease (CKD) patients due to increased thrombin generation leading to a hypercoagulable state. We previously demonstrated that inhibition of protease-activated receptor-1 (PAR-1) by vorapaxar reduces kidney fibrosis. METHODS: We used an animal model of unilateral ischemia-reperfusion injury-induced CKD to explore the tubulovascular crosstalk mechanisms of PAR-1 in acute kidney injury (AKI)-to-CKD transition. RESULTS: During the early phase of AKI, PAR-1-deficient mice exhibited reduced kidney inflammation, vascular injury, and preserved endothelial integrity and capillary permeability. During the transition phase to CKD, PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via downregulated transforming growth factor-ß/Smad signaling. Maladaptive repair in the microvasculature after AKI further exacerbated focal hypoxia with capillary rarefaction, which was rescued by stabilization of hypoxia-inducible factor and increased tubular vascular endothelial growth factor A in PAR-1-deficient mice. Chronic inflammation was also prevented with reduced kidney infiltration by both M1- and M2-polarized macrophages. In thrombin-induced human dermal microvascular endothelial cells (HDMECs), PAR-1 mediated vascular injury through activation of NF-κB and ERK MAPK pathways. Gene silencing of PAR-1 exerted microvascular protection via a tubulovascular crosstalk mechanism during hypoxia in HDMECs. Finally, pharmacologic blockade of PAR-1 with vorapaxar improved kidney morphology, promoted vascular regenerative capacity, and reduced inflammation and fibrosis depending on the time of initiation. CONCLUSIONS: Our findings elucidate a detrimental role of PAR-1 in vascular dysfunction and profibrotic responses upon tissue injury during AKI-to-CKD transition and provide an attractive therapeutic strategy for post-injury repair in AKI.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Lesiones del Sistema Vascular , Animales , Humanos , Ratones , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/tratamiento farmacológico , Células Endoteliales/metabolismo , Fibrosis , Hipoxia , Inflamación/patología , Riñón , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Daño por Reperfusión/complicaciones , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Trombina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Lesiones del Sistema Vascular/metabolismo , Lesiones del Sistema Vascular/patologíaRESUMEN
Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health concerns with increasing rates in morbidity and mortality. Transition from AKI-to-CKD is common and requires awareness in the management of AKI survivors. AKI-to-CKD transition is a main risk factor for the development of cardiovascular disease and progression to end-stage kidney disease. The mechanisms driving AKI-to-CKD transition are being explored to identify potential molecular and cellular targets for renoprotective drug interventions. Endoplasmic reticulum (ER) stress and autophagy are involved in the process of AKI-to-CKD transition. Excessive ER stress results in the persistent activation of unfolded protein response, which is an underneath cause of kidney cell death. Moreover, ER stress modulates autophagy and vice-versa. Autophagy is a degradation defensive mechanism protecting cells from malfunction. However, the underlying pathological mechanism involved in this interplay in the context of AKI-to-CKD transition is still unclear. In this review, we discuss the crosstalk between ER stress and autophagy in AKI, AKI-to-CKD transition, and CKD progression. In addition, we explore possible therapeutic targets that can regulate ER stress and autophagy to prevent AKI-to-CKD transition to improve the long-term prognosis of AKI survivors.
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Lesión Renal Aguda , Autofagia , Estrés del Retículo Endoplásmico , Insuficiencia Renal Crónica , Humanos , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Progresión de la Enfermedad , Riñón/patología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismoRESUMEN
Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD.
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Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-ß, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase.
Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Ratas , Animales , Hemo-Oxigenasa 1 , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Insuficiencia Renal Crónica/metabolismo , Riñón/metabolismo , Isquemia/complicaciones , Antiinflamatorios/farmacología , Hemo/farmacologíaRESUMEN
Epigenetic memory, which refers to the ability of cells to retain and transmit epigenetic marks to their daughter cells, maintains unique gene expression patterns. Establishing programmed epigenetic memory at each stage of development is required for cell differentiation. Moreover, accumulating evidence shows that epigenetic memory acquired in response to environmental stimuli may be associated with diverse diseases. In the field of kidney diseases, the "memory" of acute kidney injury (AKI) leads to progression to chronic kidney disease (CKD); epidemiological studies show that patients who recover from AKI are at high risk of developing CKD. The underlying pathological processes include nephron loss, maladaptive epithelial repair, inflammation, and endothelial injury with vascular rarefaction. Further, epigenetic alterations may contribute as well to the pathophysiology of this AKI-to-CKD transition. Epigenetic changes induced by AKI, which can be recorded in cells, exert long-term effects as epigenetic memory. Considering the latest findings on the molecular basis of epigenetic memory and the pathophysiology of AKI-to-CKD transition, we propose here that epigenetic memory contributing to AKI-to-CKD transition can be classified according to the presence or absence of persistent changes in the associated regulation of gene expression, which we designate "driving" memory and "priming" memory, respectively. "Driving" memory, which persistently alters the regulation of gene expression, may contribute to disease progression by activating fibrogenic genes or inhibiting renoprotective genes. This process may be involved in generating the proinflammatory and profibrotic phenotypes of maladaptively repaired tubular cells after kidney injury. "Priming" memory is stored in seemingly successfully repaired tubular cells in the absence of detectable persistent phenotypic changes, which may enhance a subsequent transcriptional response to the second stimulus. This type of memory may contribute to AKI-to-CKD transition through the cumulative effects of enhanced expression of profibrotic genes required for wound repair after recurrent AKI. Further understanding of epigenetic memory will identify therapeutic targets of future epigenetic intervention to prevent AKI-to-CKD transition.