The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice

Brown, Carolyn N.; Atwood, Daniel J.; Pokhrel, Deepak; Ravichandran, Kameswaran; Holditch, Sara J.; Saxena, Sanskriti; Miyazaki, Masaru; Nemenoff, Raphael A.; Weiser‐Evans, Mary C.M.; Ljubanović, Danica Galešić; Joy, Melanie S.; Edelstein, Charles L.

doi:10.1016/j.cellsig.2020.109605

Cited by 8 publications

(7 citation statements)

References 51 publications

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“…We believe that trametinib is a potential candidate to inhibit the pathological processes associated with cisplatin-induced kidney injury due to its ability to attenuate inflammation, oxidative stress, and cell death by interfering with the MEK/ERK pathway. Although a recent animal study reported that trametinib is ineffective against cisplatin-induced nephrotoxicity [ 20 ], our findings contradict these results. The present study aims to evaluate the potential of trametinib to mitigate these pathological processes in a mouse model of cisplatin-induced AKI.…”

Section: Introductioncontrasting

confidence: 99%

Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model

Lee,

Kim,

Leem

2024

Molecules

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Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.

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Section: Introductioncontrasting

confidence: 99%

Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model

Lee,

Kim,

Leem

2024

Molecules

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“…The expression of genes in Cluster 2 and Cluster 3 were both enhanced with the increase of ischemia degree. Genes in Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival (Pabla et al, 2015;Brown et al, 2020;Kim et al, 2020). Kim et al also reported that mice treated with PD 0332991 before IRI exhibited dramatically reduced epithelial progression through S phase 24 h after IRI and ameliorated kidney injury, as reflected by improved SCr and blood urea nitrogen levels 24 h after injury.…”

Section: Discussionmentioning

confidence: 99%

No safe renal warm ischemia time—The molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury

Chen

Wang

et al. 2022

Front. Mol. Biosci.

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Ischemic acute kidney injury (AKI) has always been a hot and difficult research topic in the field of renal diseases. This study aims to illustrate the safe warm ischemia time of kidney and the molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury. We established varying degrees of renal injury due to different ischemia time (0 min, 16 min, 18 min, 20 min, 22 min, 24 min, 26 min, 28 min, and 30 min) on unilateral (left kidney) ischemia-reperfusion injury and contralateral (right kidney) resection (uIRIx) mouse model. Mice were sacrificed 24 h after uIRIx, blood samples were harvested to detect serum creatinine (Scr), and kidney tissue samples were harvested to perform Periodic Acid-Schiff (PAS) staining and RNA-Seq. Differentially expressed genes (DEGs) were identificated, time-dependent gene expression patterns and functional enrichment analysis were further performed. Finally, qPCR was performed to validated RNA-Seq results. Our results indicated that there was no absolute safe renal warm ischemia time, and every minute of ischemia increases kidney damage. Warm ischemia 26min or above in mice makes severe kidney injury, renal pathology and SCr were both significantly changed. Warm ischemia between 18 and 26 min makes mild kidney injury, with changes in pathology and renal molecular expression, while SCr did not change. No obvious pathological changes but significant differences in molecular expression were found less than 16min warm ischemia. There are two key time intervals in the process of renal ischemia injury, 0 min–16 min (short-term) and 26 min–28 min (long-term). Gene expression of immune-related pathways were most significantly down-regulated in short-term ischemia, while metabolism-related pathways were the mainly enriched pathway in long-term ischemia. Taken together, this study provides novel insights into safe renal artery occlusion time in partial nephrectomy, and is of great value for elucidating molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury, and key genes related to metabolism and immune found in this study also provide potential diagnostic and therapeutic biomarkers for AKI.

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“…Intriguingly, we found that ERK activation seemed to be required for initiating the proliferative response of HK-2 cells to limonin. Blockade of ERK activation by U0126, a specific inhibitor of MEK 41 , 42 , abolished limonin-induced c-Myc and PCNA expression in HK-2 cells (Figure 5 , C-F). EdU incorporation assay consistently demonstrated that blockade of ERK activation abolished limonin-mediated tubular cells proliferation (Figure 5 , G-H).…”

Section: Resultsmentioning

confidence: 94%

Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury

Zhou¹,

Xiang²,

Li³

et al. 2023

Int. J. Biol. Sci.

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Acute kidney injury (AKI) is a refractory clinical syndrome with limited effective treatments. Amid AKI, activation of the extracellular signal-regulated kinase (ERK) cascade plays a critical role in promoting kidney repair and regeneration. However, a mature ERK agonist in treating kidney disease remains lacking. This study identified limonin, a member of the class of compounds known as furanolactones, as a natural ERK2 activator. Employing a multidisciplinary approach, we systemically dissected how limonin mitigates AKI. Compared to vehicles, pretreatment of limonin significantly preserved kidney functions after ischemic AKI. We revealed that ERK2 is a significant protein linked to the limonin's active binding sites through structural analysis. The molecular docking study showed a high binding affinity between limonin and ERK2, which was confirmed by the cellular thermal shift assay and microscale thermophoresis. Mechanistically, we further validated that limonin promoted tubular cell proliferation and reduced cell apoptosis after AKI by activating ERK signaling pathway in vivo . In vitro and ex vivo , blockade of ERK abolished limonin's capacity of preventing tubular cell death under hypoxia stress. Our results indicated that limonin is a novel ERK2 activator with strong translational potential in preventing or mitigating AKI.

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The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice

Cited by 8 publications

References 51 publications

Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model

Efficacy of Trametinib in Alleviating Cisplatin-Induced Acute Kidney Injury: Inhibition of Inflammation, Oxidative Stress, and Tubular Cell Death in a Mouse Model

No safe renal warm ischemia time—The molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury

Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury

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