Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury

Oh, Chang Joo; Ha, Chae-Myeong; Choi, Young Keun; Park, Sungmi; Choe, Mi Sun; Jeoung, Nam Ho; Huh, Yang Hoon; Kim, Hyo Jeong; Kweon, Hee Seok; Lee, Ji min; Lee, Sun Joo; Jeon, Jae‐Han; Harris, Robert A.; Park, Keun Gyu; Lee, In Kyu

doi:10.1016/j.kint.2016.10.011

Cited by 81 publications

(58 citation statements)

References 43 publications

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“…Nephrotoxicity is the dose-limiting adverse effect of cisplatin and interventional studies suggest that mitochondrial injury may play a critical role, as different strategies to preserve mitochondrial function were nephroprotective [106,[147][148][149][150][151]. Indeed, cisplatin downregulates kidney tubular PGC-1α in vivo and in cultured tubular cells [152][153][154]. Pyruvate dehydrogenase kinase 4 (PDK4) plays a key role in cisplatin-induced AKI, since PDK4 deficiency prevented AKI and the decrease in PGC-1α expression and mitochondrial biogenesis [154].…”

Section: Pgc-1α In Akimentioning

confidence: 99%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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Section: Pgc-1α In Akimentioning

confidence: 99%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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“…Two phenomena cause cisplatin-induced AKI, i.e., cisplatin accumulation in tubular cells and renal tubular cell injury (Fernández-Martínez et al, 2016;Oh et al, 2017). Tumor patients are prone to AKI during cisplatin treatment.…”

Section: Discussionmentioning

confidence: 99%

“…In hospitalized patients, AKI incidence has reached 5-7% and is still rising, with a mortality rate of 40%. AKI is also important risk factor for the development of chronic kidney disease (Coca et al, 2012;Oh et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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SIRT1 Mediates Effects of FGF21 to Ameliorate Cisplatin-Induced Acute Kidney Injury

Chen

Yang

et al. 2020

Front. Pharmacol.

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Acute kidney injury (AKI) is a common complication in cancer patients. Kidney function is closely related to patients' quality of life and tumor prognosis. Cisplatin is a highly effective anti-tumor drug. However, the use of cisplatin is limited by its nephrotoxicity. It has been reported that FGF21 has a renal-protective function, but the mechanisms by which it does so remain unclear. In this study, we show that the expression of FGF21 is significantly upregulated in both in vitro and in vivo cisplatin-induced AKI models. Administration of recombinant FGF21 to cisplatin-induced AKI mice resulted in significantly decreased blood urea nitrogen (BUN) and serum creatinine levels, as well as significantly reduced protein levels of kidney injury molecule-1 (TIM-1), C-caspase 3, and Bax. H&E-stained kidney sections from cisplatin-induced AKI mice treated with recombinant FGF21 showed a relatively normal renal tissue structure, a reduced number of necrotic sites and vacuolar changes, and decreased casts, suggesting alleviated renal tubular injury. Experiments with an AKI cell model (cisplatin-treated HK-2 cells) yielded similar results as the mouse model; recombinant FGF21 significantly downregulated protein expression levels of TIM-1, C-caspase 3, and Bax. Furthermore, administration of recombinant FGF21 to cisplatin-treated AKI models significantly increased SIRT1 expression, and the beneficial effects of FGF21 on kidney injury were reversed by SIRT1 knockdown. Collectively, our results suggest that SIRT1 mediates the protective effect of FGF21 on cisplatin-induced kidney injury.

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“…After being freely filtered through the glomerulus, unbound cisplatin accumulates in renal cells, especially proximal tubular cells. The accumulation of cisplatin leads to nuclear DNA damage, mitochondrial dysfunction, and tubular cell injury, resulting in cell death and causing acute kidney injury (AKI) [2-4]. …”

Section: Introductionmentioning

confidence: 99%

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

Jiao

Cai²,

Yu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data showed that the tubular β-catenin level was lower in AKI patients experiencing partial recovery than in patients experiencing complete recovery. Conclusion: The activation of the wnt/β-catenin pathway by CM protects against cisplatin-induced kidney injury, resulting in reduced apoptosis and intracellular ROS levels.

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Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury

Cited by 81 publications

References 43 publications

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

SIRT1 Mediates Effects of FGF21 to Ameliorate Cisplatin-Induced Acute Kidney Injury

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

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