Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway

Xiang, Tao; Luo, Xiaodan; Ye, Lin; Huang, Hongmi; Wu, Yuan

doi:10.1016/j.yebeh.2021.108509

Cited by 31 publications

(18 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…α-KL is normally expressed in hippocampal cells. Xiang et al injected an adenoassociated viral-mediated overexpression of klotho into the bilateral hippocampus of rats and found that the expression of the Nod-like receptor family pyrin domain containing 3, interleukin (IL)-1β and caspase-1 protein were significantly alleviated, but the activation of nuclear factor erythroid 2-related factor 2 was upregulated in the brains of the temporal lobe epilepsy model rats, which alleviated neuroinflammation, neuronal injury, and improved cognitive function (34). Additionally, α-KL was also found to have an inhibitory effect on ferroptosis in this rat model (35).…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Huang¹,

Li²,

Tan³

et al. 2022

Transl Androl Urol

View full text Add to dashboard Cite

Background: Alpha-klotho (α-KL) is not only related to the regulation of calcium-phosphorus metabolism, and fibrosis in chronic kidney disease (CKD), it is also involved in the regulation of many cognitive disorders.We conducted this study to investigate the effects of CKD on cognitive dysfunction and α-KL.Methods: Doxorubicin was used to induce a CKD model, which was validated by weight, 24-hour urine protein quantification, serum creatinine (Cr), blood urea nitrogen (BUN), and kidney hematoxylin-eosin (HE) staining. The Morris water maze (MWM) paradigm was used to assess the effects of CKD on cognitive behavior. The expression of α-KL in the hippocampus was detected using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry (IHC).Results: (I) In the CKD group, the weight of the rats increased slowly (P<0.001), 24-hour urine protein increased (P<0.05), and Cr (P=0.026) and BUN levels (P=0.003) increased; (II) HE staining showed that in the CKD group there were changes in the structure, fibrosis, and inflammatory infiltration of the renal tissues, and changes in the structure, cell necrosis, and neuronal degeneration of the hippocampus; (III) in the MWM experiment, the escape latency of the CKD group was prolonged compared to that of the control group (P=0.043, 0.023), and the number of crossing the platform was reduced (P=0.003); (IV) in the CKD group, the expressions of α-KL messenger ribonucleic acid (P=0.0005) and α-KL protein (P=0.0005) in the hippocampus were downregulated. The IHC results showed that the expression of α-KL protein in the hippocampal region III cornus ammonis (CA3) of the CKD group region was also downregulated, and the α-KL-positive cells (P=0.019) and mean optical density (P=0.015) were decreased. Conclusions:The expression of α-KL appears to effect the cognitive function of CKD rats; thus, it may be a valuable target in the treatment of CKD with cognitive impairment.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Huang¹,

Li²,

Tan³

et al. 2022

Transl Androl Urol

View full text Add to dashboard Cite

show abstract

“…A number of studies suggested that a high-fat diet induced-adiposity and insulin resistance increased cerebral oxidative stress and downregulated Nrf2 signaling [2,20,[33][34][35]. This might be the main reason that triggers the declined cognitive performance in the aged brain [20].…”

Section: Ameliorate Oxidative Stressmentioning

confidence: 99%

Cognitive Impairment in Diabetes Mellitus and Its Management by Transcription Factor Nrf2-Mediated Antioxidant Defense System

Zhou¹,

Münch²,

Chang³

2023

Importance of Oxidative Stress and Antioxidant System in Health and Disease

View full text Add to dashboard Cite

Diabetes mellitus has been an epidemic in the twenty-first century and an approximately 50% risk of diabetes predisposed to cognitive decline leading to dementia in humans. There is an urgent need to understand the pathophysiology and identify molecular targets of cognitive impairment in diabetes mellitus that might lead to improved therapy. Mounting evidence indicates that nuclear factor erythroid 2-related factor 2 (Nrf2) and its regulated downstream antioxidant genes are emerging therapeutic targets. In this chapter, we introduce cognitive dysfunction in diabetes mellitus and its hallmarks, particularly its pathological mechanisms related to oxidative stress in the brain, then justify the role of the transcription factor Nrf2-mediated antioxidant defense system in attenuating cognitive decline in diabetes mellitus. Studies on Nrf2 inducers sourced from natural products (i.e., sulforaphane, astaxanthin, resveratrol, quercetin) that have shown potent cognitive improvement in diabetic models are discussed. These studies have demonstrated that Nrf2 inducers drive the antioxidant and anti-inflammatory responses in the hippocampus region and effectively improve the spatial and memory function in diabetic rats/mice. However, evidence from large and well-designed clinical trials is warranted to support Nrf2 inducers as promising therapeutic agents in the management of cognitive impairment in diabetes mellitus.

show abstract

“…Klotho activated Nrf2 in renal, cardiovascular and neurological preclinical disease models ( Maltese et al, 2017 ; Zhu et al, 2017 ; Xing et al, 2021 ; Xiang et al, 2022 ). Nrf2 is a transcription factor that controls responses to oxidative stress and toxins ( Dinkova-Kostova et al, 2018 ; Qu et al, 2020 ; Panda et al, 2022 ).…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

View full text Add to dashboard Cite

The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

show abstract

Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway

Cited by 31 publications

References 45 publications

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Cognitive Impairment in Diabetes Mellitus and Its Management by Transcription Factor Nrf2-Mediated Antioxidant Defense System

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Contact Info

Product

Resources

About