Oligomeric Procyanidins Alleviate Cisplatin-Induced Chronic Kidney Injury by Inhibiting Neutrophil Extracellular Traps Formation and Modulating the Gut-Kidney Axis

Conceitos essenciais

Neutrophil Extracellular Traps (NETs) play a crucial role in cisplatin-induced chronic kidney disease (CKD), and oligomeric procyanidins (OPCs) offer a potential therapeutic strategy by inhibiting NETs formation, reducing inflammation, and modulating the gut-kidney axis.

Resumo

• Bibliographic Information: (Note: The provided content does not include a full citation. Please provide the source for a complete bibliographic entry.)

• Research Objective: This study investigates the role of NETs in the development of CKD induced by repeated low-dose cisplatin (RLDC) treatment and explores the therapeutic potential of OPCs in mitigating this condition.

• Methodology: The researchers used a mouse model of RLDC-induced CKD. They employed various techniques, including histological analysis, ELISA, western blotting, immunofluorescence, 16S rDNA gene sequencing, and in vitro neutrophil cultures, to investigate the mechanisms underlying CKD progression and the effects of OPCs.

• Key Findings:

  • RLDC treatment led to the accumulation of NETs in the kidneys, contributing to tubular injury, inflammation, fibrosis, and microcirculatory disturbances.
  • OPCs effectively inhibited NETs formation, reduced the expression of inflammatory cytokines (NLRP3, IL-18, IFN-γ), and improved renal function in RLDC-treated mice.
  • Cisplatin disrupted the intestinal barrier, leading to increased gut permeability and LPS leakage, which further promoted NETs formation.
  • OPCs protected the intestinal barrier, restored gut microbiota balance, and reduced LPS translocation, thereby mitigating CKD progression.

• Main Conclusions:

  • NETs play a critical role in the pathogenesis of RLDC-induced CKD by promoting inflammation, microthrombosis, and fibrosis.
  • OPCs effectively alleviate CKD progression by inhibiting NETs formation, protecting the intestinal barrier, and modulating the gut-kidney axis.

• Significance: This study provides novel insights into the mechanisms of cisplatin-induced CKD and highlights the therapeutic potential of OPCs as a promising treatment strategy for this condition.

• Limitations and Future Research: Further research is needed to determine the optimal dosage and long-term effects of OPCs in clinical settings. Investigating the specific interactions between gut microbiota, NETs, and CKD progression could lead to more targeted therapeutic interventions.

Estatísticas

RLDC regimen involved weekly administration of 7 mg/kg cisplatin for four weeks.
OPCs were administered at a dose of 100 mg/kg.
PAD4-/- mice, deficient in NETs formation, showed significantly reduced renal injury compared to wild-type mice after RLDC treatment.
OPCs treatment restored the levels of tight junction proteins (Claudin-1, ZO-1, Occludin) in the intestines of RLDC-treated mice.
RLDC treatment reduced the abundance of beneficial gut bacteria like Muribaculaceae, Akkermansia, and Clostridia-UCG-014, which were restored by OPCs.
OPCs decreased the levels of neutrophil ROS and NETs formation in in vitro experiments.

Citações

"Cisplatin consistently maintains low endotoxemia in vivo by impairing the intestinal barrier, leading to continuous induction of NETosis by LPS."
"Elevated levels of NETs in the kidney result in NLRP3-associated inflammation on the one hand and ischemia and hypoxia on the other, which ultimately lead to apoptosis and interstitial fibrosis in renal parenchymal cells."
"In our studies, OPCs protected the kidneys by restoring the physical and ecological structure of the gut, thereby disrupting the positive feedback pathway of the gut‒kidney axis."

Principais Insights Extraídos De

Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis

by Luan,Y., He,... às www.biorxiv.org 09-07-2024

https://www.biorxiv.org/content/10.1101/2024.09.03.610977v1

Perguntas Mais Profundas

How might the findings of this study influence the development of preventative measures for CKD in patients undergoing long-term cisplatin treatment?

This study highlights the critical role of Neutrophil Extracellular Traps (NETs) and the gut-kidney axis in the development of chronic kidney disease (CKD) induced by repeated low-dose cisplatin (RLDC) treatment. This understanding opens several avenues for developing preventative measures:

Targeting NETs Formation: The study demonstrates that inhibiting NETs formation using approaches like PAD4 inhibitors or OPCs can effectively alleviate CKD progression. This suggests that incorporating such agents into the treatment regimen of patients undergoing long-term cisplatin therapy could potentially prevent or delay CKD onset. Clinical trials would be needed to confirm the efficacy and safety of these approaches in humans.

Modulating the Gut Microbiota: The study emphasizes the importance of the gut-kidney axis, where gut dysbiosis induced by cisplatin contributes to CKD development. This suggests that strategies aimed at maintaining a healthy gut microbiota during cisplatin treatment could be beneficial. These strategies could include:

Dietary interventions: Promoting a fiber-rich diet that favors the growth of beneficial bacteria like Bacteroidetes.
Probiotics and prebiotics: Administering specific probiotic strains or prebiotic supplements to restore the balance of the gut microbiota.
Fecal microbiota transplantation (FMT): While more invasive, FMT could be considered in specific cases to repopulate the gut with a healthy microbial community.

Combination Therapies: The multifaceted nature of CKD development suggests that a combination of preventative measures targeting both NETs formation and gut dysbiosis might be most effective. For instance, combining OPCs with dietary interventions or probiotics could provide synergistic protection against CKD.

Early Detection and Monitoring: The study underscores the need for early detection and monitoring of CKD in patients receiving cisplatin. This could involve regular assessment of renal function markers, gut microbiota composition, and NETs levels. Early intervention based on these markers could significantly improve patient outcomes.

This study provides a strong foundation for future research and clinical trials to develop effective preventative strategies for CKD in the context of long-term cisplatin treatment.

Could other factors besides NETs formation and gut dysbiosis contribute to the development of CKD in this model, and how might their roles be investigated?

While the study convincingly demonstrates the importance of NETs and gut dysbiosis in RLDC-induced CKD, other contributing factors could be at play. These include:

Direct Cisplatin Toxicity: Even at low doses, cisplatin can directly damage renal tubular epithelial cells, leading to cell death and inflammation. Investigating the specific molecular pathways of direct cisplatin toxicity, independent of NETs or gut dysbiosis, could reveal additional therapeutic targets. This could involve:

In vitro studies: Using cultured renal cells to assess the direct effects of cisplatin on cell viability, apoptosis, and inflammatory signaling pathways.
Gene expression profiling: Comparing gene expression patterns in renal tissue from RLDC-treated mice with and without interventions targeting NETs or gut dysbiosis to identify pathways specifically affected by direct cisplatin toxicity.

Oxidative Stress and Mitochondrial Dysfunction: Cisplatin is known to induce oxidative stress and impair mitochondrial function, both of which contribute to CKD progression. Assessing the role of antioxidants or mitochondria-targeted therapies in mitigating RLDC-induced CKD, in addition to NETs and gut modulation, could provide further insights. This could involve:

Measuring oxidative stress markers: Analyzing markers like malondialdehyde (MDA) and glutathione (GSH) in renal tissue to assess the extent of oxidative damage.
Evaluating mitochondrial function: Assessing mitochondrial respiration rates and ATP production in renal cells to determine the impact of RLDC and potential interventions.

Immune Cell Infiltration and Activation: Beyond neutrophils, other immune cells like macrophages and T cells can infiltrate the kidneys and contribute to inflammation and fibrosis. Investigating the specific roles of these cells and potential immunomodulatory therapies could be beneficial. This could involve:

Flow cytometry analysis: Characterizing the immune cell populations infiltrating the kidneys in RLDC-treated mice and assessing the impact of interventions.
Cytokine profiling: Measuring the levels of pro-inflammatory and anti-inflammatory cytokines in renal tissue to understand the immune landscape and potential therapeutic targets.

Genetic Predisposition: Genetic factors could influence an individual's susceptibility to cisplatin-induced CKD. Investigating potential genetic polymorphisms associated with increased risk could help identify patients who might benefit from more aggressive preventative measures. This could involve:

Genome-wide association studies (GWAS): Identifying genetic variations associated with CKD development in patients receiving cisplatin.
Candidate gene approaches: Investigating specific genes involved in drug metabolism, oxidative stress response, or inflammation that might influence susceptibility.

By exploring these additional factors, we can gain a more comprehensive understanding of RLDC-induced CKD and develop more targeted and effective preventative strategies.

If the gut-kidney axis plays such a significant role in CKD development, what broader implications might this have for our understanding of chronic diseases in general?

The significant role of the gut-kidney axis in CKD development, as highlighted by this study, has profound implications for our understanding of chronic diseases in general. It reinforces the concept that:

Chronic Diseases are Interconnected: The gut-kidney axis exemplifies the interconnectedness of organ systems and how dysfunction in one organ can have cascading effects on others. This emphasizes the need to move away from an organ-centric view of disease and adopt a more holistic, systems biology approach.

The Gut Microbiota is a Key Player: The study reinforces the emerging understanding of the gut microbiota as a crucial regulator of health and disease. Dysbiosis, or an imbalance in the gut microbial community, is increasingly linked to a wide range of chronic conditions, including cardiovascular disease, metabolic disorders, autoimmune diseases, and even neurodegenerative diseases.

Personalized Medicine is Essential: The composition of the gut microbiota is highly individual and influenced by factors like genetics, diet, and environmental exposures. This suggests that personalized approaches to disease prevention and treatment, tailored to an individual's gut microbiota profile, could be more effective.

Lifestyle Interventions are Powerful: Diet and lifestyle factors significantly impact the gut microbiota. This emphasizes the importance of lifestyle interventions, such as promoting a healthy diet, regular exercise, and stress management, in preventing and managing chronic diseases.

New Therapeutic Avenues: Targeting the gut microbiota through approaches like probiotics, prebiotics, FMT, or even engineered bacteria, holds immense therapeutic potential for a wide range of chronic diseases.

The findings of this study, particularly the role of the gut-kidney axis, underscore the need for a paradigm shift in how we approach chronic diseases. By understanding the complex interplay between organ systems, particularly the gut microbiota, we can develop more effective and personalized strategies for preventing and treating these conditions.