Cisplatin nephrotoxicity as a model of chronic kidney disease

Shi, Mingjun; McMillan, Kathryn L.; Wu, Jia‐Zhu; Gillings, Nancy; Flores, Brianna; Moe, Orson W.; Hu, Ming

doi:10.1038/s41374-018-0063-2

Cited by 68 publications

(48 citation statements)

References 71 publications

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“…For KL administration, the recombinant mouse KL protein (R&D Systems, USA; 10 μg/kg) dissolved in phosphate-buffered saline (PBS, 0.01 mM) was injected IP 6 h prior to PQ treatment followed by every other day injection for 7 days. The dosage of KL was selected based on previous studies [18]. The mice were randomly assigned to four groups of 12 and studied concomitantly.…”

Section: Methodsmentioning

confidence: 99%

Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis

Zhang

Nian

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Acute lung injury (ALI) induced by paraquat (PQ) progresses rapidly with high mortality; however, there is no effective treatment, and the specific mechanism is not well understood. The antiaging protein klotho (KL) has multiple functions and exerts significant influences on various pathophysiological processes. This work evaluated the impact of KL on PQ-induced ALI and investigated its underlying mechanisms. As for in vivo research, C57BL/6 mice were treated with PQ (30 mg/kg) intraperitoneal (IP) injection to create a toxicity model of ALI (PQ group). The mice were divided into control group, KL group, PQ group, and PQ+KL group. For in vitro experiment, A549 cells were incubated with or without KL and then treated in the presence or absence of PQ for 24 h. In vivo result indicated that KL reduced the mortality, reduced IL-1β and IL-6 in the bronchoalveolar lavage fluid (BALF), attenuated ALI, and decreased apoptosis in situ. In vitro result revealed that KL significantly improved cell viability, reduced the levels of IL-1β and IL-6 in culture supernatants, suppressed cell apoptosis, inhibited caspase-3 activation, and enhanced mitochondrial membrane potential (ΔΨm) after PQ treatment. Besides, KL effectively abated reactive oxygen species (ROS) production, improved GSH content, and lowered lipid peroxidation in PQ-exposed A549 cells. Further experiments indicated that phosphorylated JNK and P38 MAPK was increased after PQ treatment; however, KL pretreatment could significantly lower the phosphorylation of P38 MAPK. Suppression of P38 MAPK improved cell viability, alleviated inflammatory response, and reduced apoptosis-related signals; however, it had no obvious effect on the production of ROS. Treatment with N-acetylcysteine (NAC), a classic ROS scavenger, could suppress ROS production and P38 MAPK activation. These findings suggested that KL could alleviate PQ-caused ALI via inhibiting ROS/P38 MAPK signaling-regulated inflammatory responses and mitochondria-dependent apoptosis.

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Section: Methodsmentioning

confidence: 99%

Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis

Zhang

Nian

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The mice developed LVH and cardiac fibrosis. This model resembles the transition from acute kidney injury to chronic renal failure and thus displays a promising approach to study underlying mechanisms in humans [93].…”

Section: Chemically Induced Modelsmentioning

confidence: 99%

Cardiac Remodeling in Chronic Kidney Disease

Kaesler

Babler

Floege

et al. 2020

Toxins

100

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Cardiac remodeling occurs frequently in chronic kidney disease patients and affects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between different cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and/or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics.

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“…The calcium concentration in tissues was measured using the o-cresolphthalein complexone method (Sigma-Aldrich, St. Louis, MO). 45,49 The calcium content (μg/mg protein) was quantified by normalization to protein concentration determined by Bradford protein assay.…”

Section: Von Kossa Staining and Calcium Content Measurementmentioning

confidence: 99%

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

et al. 2020

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Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein αKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and αKlotho, we used the BK/BK mouse (homozygous for mutant Becn1 F121A ) with increased autophagic flux, and αKlothohypomorphic mouse (kl/kl) with impaired urinary Pi excretion, low autophagy, and premature organ dysfunction. BK/BK mice live longer than WT littermates, and have heightened phosphaturia from downregulation of two key NaPi cotransporters in the kidney. The multi-organ failure in kl/kl mice was rescued in the double-mutant BK/ BK;kl/kl mice exhibiting lower plasma Pi, improved weight gain, restored plasma and renal αKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1 F121A was abolished by chronic high-Pi diet which also shortened life span in the BK/BK;kl/kl mice. Pi promoted beclin 1 binding to its negative regulator BCL2, which impairs autophagy flux. Pi downregulated αKlotho, which also independently impaired autophagy. In conclusion, Pi, αKlotho, and autophagy interact intricately 3130 | SHI et al.

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Cisplatin nephrotoxicity as a model of chronic kidney disease

Cited by 68 publications

References 71 publications

Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis

Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis

Cardiac Remodeling in Chronic Kidney Disease

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

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