Cisplatin Nephrotoxicity: Novel Insights Into Mechanisms and Preventative Strategies

Motwani, Shveta S.; Kaur, Sukhbir; Kitchlu, Abhijat

doi:10.1016/j.semnephrol.2023.151341

Cited by 16 publications

(3 citation statements)

References 90 publications

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“…Cisplatin, also known as CDDP, is a commonly used chemotherapy medication. However, its use as an anti-cancer drug is limited due to its toxicity towards the kidneys and the potential risk of causing sudden kidney damage known as CI-AKI [22]. The occurrence of CI-AKI is closely associated with the accumulation of ROS and resulting oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling

Sun,

Chang,

Jiang

et al. 2024

Molecules

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Derived from hazelnuts, hazel leaf has been utilized in traditional folk medicine for centuries in countries such as Portugal, Sweden, and Iran. In our previous investigations, we conducted a preliminary assessment of the hazel leaf polyphenol extract (referred to as ZP) and identified nine compounds, such as kaempferol and chlorogenic acid, in its composition. ZP has shown promising properties as an antioxidant and anti-inflammatory agent. Our research has revealed that ZP has protective effects against cisplatin-induced acute kidney injury (AKI). We conducted a comprehensive examination of both the pathological and ultrastructural aspects and found that ZP effectively ameliorated renal tissue lesions and mitigated mitochondrial damage. Moreover, ZP significantly suppressed malondialdehyde levels while increasing glutathione and catalase concentrations in the kidneys of AKI-induced mice. ZP decreased the number of apoptotic cells and decreased pro-apoptotic protein expression in the kidneys of mice and human renal tubular epithelial cells (HK-2). Furthermore, treatment with ZP increased the levels of proteins marking anti-ferroptosis, such as GPX4, FTH1, and FSP1, in experiments both in vivo and in vitro. We elucidated the underlying mechanisms of ZP’s actions, revealing its inhibitory effect on Yap phosphorylation and its regulation of Lats expression, which exert a protective influence on the kidneys. Furthermore, we found that inhibiting the Hippo pathway compromised ZP’s nephroprotective effects in both in vitro and in vivo studies. In summary, this research shows that ZP exhibits renoprotective properties, effectively reducing oxidative damage, apoptosis, and ferroptosis in the kidneys by targeting the Hippo pathway.

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Section: Discussionmentioning

confidence: 99%

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling

Sun,

Chang,

Jiang

et al. 2024

Molecules

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“…Single-cell RNA-sequencing data show PB cells express a broad range of genes associated with proximal tubule physiological functions, such as sodium bicarbonate transport (SLC4A4, 71.5% of cells from PB), monocarboxylate and iodide transport (SLC5A8, 79.0% of cells from PB), amino acid transport (SLC3A1, 71.8% of cells from PB), and copper transport (SLC31A1, 71.0% cells from PB) (Figure S6c). SLC31A1 has also been shown to be important for uptake of cisplatin, a chemotherapeutic with severe nephrotoxic side-effects [44][45][46][47][48][49][50][51][52][53][54] . Recent studies show that organoids are sensitive to cisplatin and respond by activating early proximal tubule injury marker KIM1/HAVCR1 expression and display evidence of DNA damage [12][13][14] .…”

Section: Modeling Cisplatin-induced Injury and Proximal Tubule Physio...mentioning

confidence: 99%

Stepwise developmental mimicry generates proximal-biased kidney organoids

Schnell,

Miao,

Achieng

et al. 2024

Preprint

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The kidney maintains body fluid homeostasis by reabsorbing essential compounds and excreting waste. Proximal tubule cells, crucial for renal reabsorption of a range of sugars, ions, and amino acids, are highly susceptible to damage, leading to pathologies necessitating dialysis and kidney transplants. While human pluripotent stem cell-derived kidney organoids are used for modeling renal development, disease, and injury, the formation of proximal nephron cells in these 3D structures is incomplete. Here, we describe how to drive the development of proximal tubule precursors in kidney organoids by following a blueprint ofin vivohuman nephrogenesis. Transient manipulation of the PI3K signaling pathway activates Notch signaling in the early nephron and drives nephrons toward a proximal precursor state. These “proximal-biased” (PB) organoid nephrons proceed to generate proximal nephron precursor cells. Single-cell transcriptional analyses across the organoid nephron differentiation, comparing control and PB types, confirm the requirement of transient Notch signaling for proximal development. Indicative of functional maturity, PB organoids demonstrate dextran and albumin uptake, akin toin vivoproximal tubules. Moreover, PB organoids are highly sensitive to nephrotoxic agents, display an injury response, and drive expression ofHAVCR1/KIM1, an early proximal-specific marker of kidney injury. Injured PB organoids show evidence of collapsed tubules, DNA damage, and upregulate the injury-response markerSOX9. The PB organoid model therefore has functional relevance and potential for modeling mechanisms underpinning nephron injury. These advances improve the use of iPSC-derived kidney organoids as tools to understand developmental nephrology, model disease, test novel therapeutics, and for understanding human renal physiology.

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“…Cisplatin is a commonly used chemotherapeutic agent for various tumors. Nephrotoxicity is a common toxicity of cisplatin as renal tubule cells are sensitive to cisplatin accumulation (Motwani et al, 2022 ). A study showed that the antioxidant property of EA elicited beneficial effects on cisplatin‐induced nephrotoxicity and gonadotoxicity.…”

Section: Protective Effects Of Ea Against Drugs Toxicitiesmentioning

confidence: 99%

An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals

Jamshidi,

Roohbakhsh,

Karimi

2023

Food Science & Nutrition

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Ellagic acid (EA) is a polyphenol extracted from many plants. EA modulates inflammatory mediators via antioxidant mechanisms, such as catalase (CAT) activities, superoxide dismutase (SOD), enhancement, increase in glutathione (GSH), and lipid peroxidation (LPO) suppression. EA has anti‐apoptotic properties that are thought to be mediated by regulating the expression of B‐cell lymphoma 2 (Bcl‐2), Bcl‐2‐associated X protein (Bax), and caspase‐3. In this article, we surveyed the literature dealing with the protective effects of EA against different heavy metals, drugs, and natural toxins. The findings indicated that EA has remarkable protective properties against various toxicants. Its protective effects were mostly mediated via normalizing lipid metabolism, oxidative stress, and inflammatory mediators, for example, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and IL‐1β. The results of this study showed that EA has significant protective effects against a varied range of compounds, either chemical or natural. These effects are mainly mediated via intensifying the antioxidant defense system. However, other mechanisms such as inhibition of inflammatory responses and suppression of apoptosis are important.

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Cisplatin Nephrotoxicity: Novel Insights Into Mechanisms and Preventative Strategies

Cited by 16 publications

References 90 publications

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling

Hazel Leaf Polyphenol Extract Alleviated Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis through Inhibiting Hippo Signaling

Stepwise developmental mimicry generates proximal-biased kidney organoids

An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals

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