July 23, 2024

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Unexpected Discovery: “Miracle Drug” Metformin Exhibits Kidney Toxicity

Unexpected Discovery: “Miracle Drug” Metformin Exhibits Kidney Toxicity



Unexpected Discovery: “Miracle Drug” Metformin Exhibits Kidney Toxicity

The global elderly population is projected to reach 2 billion by 2050. This signifies a growing challenge of aging worldwide.

Aging is a significant risk factor for the development of common chronic diseases, with 90% of individuals aged 65 and older suffering from at least one chronic ailment. Previous research has indicated various strategies for combating aging, such as the use of young blood to restore memory loss and impaired physical abilities associated with aging, calorie-restricted diets, and certain drugs including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, which may contribute to extending lifespan and healthspan.

Notably, kidney disease is a key risk factor for human longevity. Over 10% of adults globally suffer from kidney diseases, with Acute Kidney Injury (AKI) being the most common cause of systemic organ dysfunction. Furthermore, AKI patients are at a high risk of developing Chronic Kidney Disease (CKD), kidney failure, and other types of organ failure. Yet, the precise mechanisms of AKI remain poorly understood, and specific drugs for treating various kidney diseases are lacking. Thus, the prevention and treatment of kidney diseases represent an urgent public health issue.

On October 18, 2023, researchers from Zhejiang University School of Medicine, with Dr. Cai Zhaoxian and doctoral students Wu Xiaotian and Song Zijun as joint first authors, published a study titled “Metformin Potentiates Nephrotoxicity by Promoting NETosis in Response to Renal Ferroptosis” in the journal Cell Discovery.

This groundbreaking study unexpectedly discovered that the longevity “miracle drug” metformin significantly exacerbates Acute Kidney Injury (AKI) and even has potentially lethal side effects. The research also delves deep into the molecular mechanisms of metformin’s kidney toxicity. This discovery provides crucial scientific evidence for the evaluation and guidance of metformin’s clinical application.

Researchers noted that metformin is a frontline medication for diabetes treatment globally, and an increasing body of research suggests its potential benefits in different diseases, including anti-aging. This finding offers important scientific support for the assessment and guidance of metformin’s clinical applications, and the team is actively exploring its pros and cons in clinical use in collaboration with other experts.

Unexpected Discovery: "Miracle Drug" Metformin Exhibits Kidney Toxicity

Researchers further emphasized that global aging has been a focal and challenging area of scientific research, often accompanied by aging and damage to organs and tissues. In clinical practice, assessing kidney function is considered a sentinel for evaluating a patient’s overall health. Therefore, studying the prevention and treatment of kidney injuries from an anti-aging perspective may contribute to human health to some extent.

To address this question and find potential lifespan-extending drugs beneficial for kidney diseases, the research team explored the effects of five potential anti-aging drugs in relevant mouse models, with a focus on metformin. Metformin is a biguanide derivative first described nearly a century ago, known for its glucose-lowering effects by inhibiting hepatic glucose production. It is currently a frontline treatment for type 2 diabetes. Recent studies suggest that metformin may have potential benefits for various diseases and symptoms, including cancer, obesity, liver disease, cardiovascular diseases, and anti-aging, making it one of the most promising drugs for extending lifespan.

Given these potential benefits, metformin is often recommended for use by individuals without diabetes in clinical practice. However, the exact activity of metformin in Acute Kidney Injury (AKI) remains unclear.

In this study, the research team unexpectedly found that even low doses of metformin exacerbated experimentally induced AKI in mice and increased their mortality. Researchers told “Biological World” that the team was surprised by this finding and encountered challenges in exploring the mechanism further. The most striking moment came when they found the key target proteins and struggled to explain and connect the mouse phenotypes. After multiple late-night discussions and analyses by team members and assistance from collaborators, they found a breakthrough more than a year later.

Through single-cell transcriptome analysis, the research team found that treating AKI with metformin led to the death of renal parenchymal cells and an increase in neutrophils. Further studies revealed that programmed cell death, including ferroptosis, occurred in renal parenchymal cells, and blocking ferroptosis or depleting neutrophils prevented metformin-induced kidney toxicity.

The research team also elucidated the specific mechanism. After inducing AKI in mice, renal parenchymal cells underwent programmed cell death, including ferroptosis. They secreted a large amount of NGAL protein, which formed a metformin-iron-NGAL complex in circulation and bound to the CXCR4 receptor on the surface of neutrophils, causing their chemotaxis and mediating NETosis (a mechanism of neutrophils combating infection), further exacerbating kidney damage.

Finally, the research team demonstrated that reducing iron levels had a protective effect on kidney injuries, supporting the notion that iron plays a vital role in metformin-induced Acute Kidney Injury (AKI).

Unexpected Discovery: "Miracle Drug" Metformin Exhibits Kidney Toxicity

Researchers stressed that this study, conducted in a mouse model, revealed the kidney side effects of metformin, providing a more reliable basis for assessing metformin’s clinical applicability from a fundamental research perspective. Mechanistically, the interaction between metformin and the body’s iron elements exacerbated the death of mouse renal parenchymal cells, leading to an immune response involving neutrophils’ NETosis. These findings highlight the close interplay between cell-to-cell reactions and cellular activities, representing a significant breakthrough in this research.

From a clinical perspective, this study suggests that patients receiving metformin treatment should monitor not only their kidney function but also NGAL protein levels and iron levels to mitigate potential clinical kidney toxicity risks. Researchers stated that this research underscores the potential kidney risks associated with metformin use, even in non-diabetic individuals, providing a theoretical basis for investigating the global prevalence of diabetes and kidney diseases. Additionally, this study opens the door for further research into the kidney side effects of many medications.

Link to the paper

Unexpected Discovery: “Miracle Drug” Metformin Exhibits Kidney Toxicity

(source:internet, reference only)


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