Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis
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Curated by eLife
eLife Assessment
This important study provides evidence for the role of neutrophil extracellular traps in chronic kidney damage (CKD) induced by chemotherapy and suggests a therapeutic approach to mitigate the kidney pathology caused by the NETs. The study utilizes a sound murine in vivo model of CKD with low-dose administration cisplatin and a genetic model for impairment of NET formation by deletion of the enzyme Pad4. In its current form, the study was seen as incomplete as there is not yet formal demonstration of NET production by neutrophils in the model of CKD used. Additionally, the accuracy and clarity of data presentation could be improved.
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Abstract
Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora
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eLife Assessment
This important study provides evidence for the role of neutrophil extracellular traps in chronic kidney damage (CKD) induced by chemotherapy and suggests a therapeutic approach to mitigate the kidney pathology caused by the NETs. The study utilizes a sound murine in vivo model of CKD with low-dose administration cisplatin and a genetic model for impairment of NET formation by deletion of the enzyme Pad4. In its current form, the study was seen as incomplete as there is not yet formal demonstration of NET production by neutrophils in the model of CKD used. Additionally, the accuracy and clarity of data presentation could be improved.
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Reviewer #1 (Public review):
Summary:
Chemotherapy-induced chronic kidney injury is a significant and growing concern, as it can lead to long-term renal damage and compromised kidney function. The authors have highlighted an important aspect of this issue by evaluating the potential protective effects of OPCs against cisplatin-induced kidney injury. They propose that OPCs may mitigate renal damage by reducing NET formation, which could improve kidney function.
Strengths:
The study addressed a significant issue in the field of chemotherapy-induced kidney injury. The use of multiple markers and experimental methods provided a comprehensive exploration of the impact of OPCs on kidney damage. This approach allowed for a nuanced understanding of how OPCs might mitigate renal injury by reducing NET formation and improving kidney function.
Weak…
Reviewer #1 (Public review):
Summary:
Chemotherapy-induced chronic kidney injury is a significant and growing concern, as it can lead to long-term renal damage and compromised kidney function. The authors have highlighted an important aspect of this issue by evaluating the potential protective effects of OPCs against cisplatin-induced kidney injury. They propose that OPCs may mitigate renal damage by reducing NET formation, which could improve kidney function.
Strengths:
The study addressed a significant issue in the field of chemotherapy-induced kidney injury. The use of multiple markers and experimental methods provided a comprehensive exploration of the impact of OPCs on kidney damage. This approach allowed for a nuanced understanding of how OPCs might mitigate renal injury by reducing NET formation and improving kidney function.
Weaknesses:
The hypothesis is intriguing and relevant. However, the study encounters challenges, such as incomplete evidence and discrepancies between the text and data. Addressing these issues is crucial to improving the overall study's conclusions. The paper can potentially advance the understanding of therapeutic strategies for chemotherapy-induced kidney injury. Nonetheless, a clearer presentation of the data is necessary for it to have a substantial impact.
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Reviewer #2 (Public review):
Summary:
The authors aimed to understand the mechanisms underlying chronic kidney disease (CKD) induced by cisplatin treatment. Acute or chronic kidney diseases are major adverse effects of cisplatin chemotherapy for cancer, which limits the treatment's efficacy. Understanding the disease's genesis is fundamental to identifying targets for preventing or treating these conditions.
Strengths:
The authors employed an in vivo model of cisplatin-induced chronic kidney disease (CKD) in mice, which displayed similar adverse effects of the therapy as seen in humans. The model called repeated low-dose cisplatin (RLCD), caused similar tissue and functional damage in the kidneys, led to harmful effects on the intestines by altering the microbiota and epithelial cell barrier, and impaired systemic vascular blood flow.
Th…
Reviewer #2 (Public review):
Summary:
The authors aimed to understand the mechanisms underlying chronic kidney disease (CKD) induced by cisplatin treatment. Acute or chronic kidney diseases are major adverse effects of cisplatin chemotherapy for cancer, which limits the treatment's efficacy. Understanding the disease's genesis is fundamental to identifying targets for preventing or treating these conditions.
Strengths:
The authors employed an in vivo model of cisplatin-induced chronic kidney disease (CKD) in mice, which displayed similar adverse effects of the therapy as seen in humans. The model called repeated low-dose cisplatin (RLCD), caused similar tissue and functional damage in the kidneys, led to harmful effects on the intestines by altering the microbiota and epithelial cell barrier, and impaired systemic vascular blood flow.
The authors demonstrated that the detrimental effects on the intestinal barrier led to the release of bacterial compounds into the circulation, which, in association with reactive oxygen species formed by the inflammatory and oxidative action of cisplatin, activated blood, and kidney neutrophils to release neutrophil extracellular traps (NETs). In turn, they suggested circulating NETs migrated into kidney tissue, causing damage. Moreover, they showed NETs are capable of trapping coagulation factors responsible for impaired systemic blood flow.
These conclusions were primarily based on reduced CKD symptoms and vascular damage in genetically modified animals that do not form NETs, as well as the observation that a bacterial compound (lipopolysaccharide) associated with cisplatin induces NET formation in isolated neutrophils. Moreover, treating animals with an anti-inflammatory and antioxidant natural compound simultaneously with cisplatin administration abolished the harmful effects on the kidneys and intestines.
The authors conclude that the intestinal damage and inflammatory properties of cisplatin lead to NET release, which, in turn, is responsible for the kidney and vascular damage evoked by cisplatin treatment.
Hence, the manuscript employs a well-designed experimental model and covers several important manifestations of cisplatin toxicity. It also uses genetically deficient mice to demonstrate the involvement of NETs in the development of chronic kidney disease (CKD)
Weaknesses:
Overall, the work was well executed. However, a few aspects require additional experiments to confirm the conclusions. The involvement of NETs in the genesis of CKD is unquestionable; nonetheless, the roles of locally induced versus circulating NETs, as well as the translation of in vitro NET release to in vivo CKD genesis, need further evaluation. Additionally, the primary mechanism of the natural anti-inflammatory compound used appears to be antioxidative, which does not promote the formation of reactive oxygen species necessary for NET formation. It is not clear in the title.
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