Neurologic complications, such as cognitive and emotional dysfunction, have frequently been observed in chronic kidney disease (CKD) patients. Previous research shows that uremic toxins play a role in the pathogenesis of CKD-associated cognitive impairment. Since astrocytes contribute to the protection and survival of neurons, astrocyte function and brain metabolism may contribute to the pathogenesis of neurodegeneration. Indoxyl sulfate (IS) is the most popular uremic toxin. However, how IS-induced astrocyte injury brings about neurologic complications in CKD patients has not been elucidated. Methods: The rate of extracellular acidification was measured in astrocytes when IS (0.5–3 mM, 4 or 7 days) treatment was applied. The hexokinase 1 (HK1), pyruvate kinase isozyme M2 (PKM2), pyruvate dehydrogenase (PDH), and phosphofructokinase (PFKP) protein levels were also measured. The activation of the apoptotic pathway was investigated using a confocal microscope, fluorescence- activated cell sorting, and cell three-dimensional imaging was used. Results: In astrocytes, IS affected glycolysis in not only dose-dependently but also time-dependently. Additionally, HK1, PKM2, PDH, and PFKP levels were decreased in IS-treated group when compared to the control. The results were prominent in cases with higher doses and longer exposure duration. The apoptotic features after IS treatment were also observed. Conclusion: Our results showed that the inhibition of glycolysis by IS in astrocytes leads to cell death via apoptosis. Specifically, longterm and higher-dose exposures had more serious effects on astrocytes. Our results suggest that the glycolysis pathway and related targets could provide a novel approach to cognitive dysfunction in CKD patients.

In Harrison’s Principles of Internal Medicine, human understanding is emphasized as one of three necessary characteristics that a physician must have. Inflammation, which is caused by inflammatory inducers (inf-ids), is a fundamental feature of disease at the cellular and molecular levels. Inflammation protects the body, but excessive or prolonged inflammation can be damaging and can cause disease. Humans are repeatedly exposed to external and internal environmental factors that generate inf-ids throughout their lives. External environmental factors include microbial and non-microbial inf-ids, as well as stressors that inevitably arise during social interactions. Internal environmental factors include the adaptive physiological response that is present from birth. Inf-ids may also be produced by the four-step habit loop, which consists of a cue (e.g., stressor), emotions, routine act (adaptive response), and a reward. Immune cells in the circulatory system and in tissues may have positive and negative effects in inflammatory responses. However, low-grade inflammation may be difficult to detect. We propose a model of disease development that integrates external and internal environmental factors from the perspective of human understanding.

Neurologic complications, such as cognitive and emotional dysfunction, have frequently been observed in chronic kidney disease (CKD) patients. Previous research shows that uremic toxins play a role in the pathogenesis of CKD-associated cognitive impairment. Since astrocytes contribute to the protection and survival of neurons, astrocyte function and brain metabolism may contribute to the pathogenesis of neurodegeneration. Indoxyl sulfate (IS) is the most popular uremic toxin. However, how IS-induced astrocyte injury brings about neurologic complications in CKD patients has not been elucidated. Methods: The rate of extracellular acidification was measured in astrocytes when IS (0.5–3 mM, 4 or 7 days) treatment was applied. The hexokinase 1 (HK1), pyruvate kinase isozyme M2 (PKM2), pyruvate dehydrogenase (PDH), and phosphofructokinase (PFKP) protein levels were also measured. The activation of the apoptotic pathway was investigated using a confocal microscope, fluorescence- activated cell sorting, and cell three-dimensional imaging was used. Results: In astrocytes, IS affected glycolysis in not only dose-dependently but also time-dependently. Additionally, HK1, PKM2, PDH, and PFKP levels were decreased in IS-treated group when compared to the control. The results were prominent in cases with higher doses and longer exposure duration. The apoptotic features after IS treatment were also observed. Conclusion: Our results showed that the inhibition of glycolysis by IS in astrocytes leads to cell death via apoptosis. Specifically, longterm and higher-dose exposures had more serious effects on astrocytes. Our results suggest that the glycolysis pathway and related targets could provide a novel approach to cognitive dysfunction in CKD patients.

In Harrison’s Principles of Internal Medicine, human understanding is emphasized as one of three necessary characteristics that a physician must have. Inflammation, which is caused by inflammatory inducers (inf-ids), is a fundamental feature of disease at the cellular and molecular levels. Inflammation protects the body, but excessive or prolonged inflammation can be damaging and can cause disease. Humans are repeatedly exposed to external and internal environmental factors that generate inf-ids throughout their lives. External environmental factors include microbial and non-microbial inf-ids, as well as stressors that inevitably arise during social interactions. Internal environmental factors include the adaptive physiological response that is present from birth. Inf-ids may also be produced by the four-step habit loop, which consists of a cue (e.g., stressor), emotions, routine act (adaptive response), and a reward. Immune cells in the circulatory system and in tissues may have positive and negative effects in inflammatory responses. However, low-grade inflammation may be difficult to detect. We propose a model of disease development that integrates external and internal environmental factors from the perspective of human understanding.

Neurologic complications, such as cognitive and emotional dysfunction, have frequently been observed in chronic kidney disease (CKD) patients. Previous research shows that uremic toxins play a role in the pathogenesis of CKD-associated cognitive impairment. Since astrocytes contribute to the protection and survival of neurons, astrocyte function and brain metabolism may contribute to the pathogenesis of neurodegeneration. Indoxyl sulfate (IS) is the most popular uremic toxin. However, how IS-induced astrocyte injury brings about neurologic complications in CKD patients has not been elucidated. Methods: The rate of extracellular acidification was measured in astrocytes when IS (0.5–3 mM, 4 or 7 days) treatment was applied. The hexokinase 1 (HK1), pyruvate kinase isozyme M2 (PKM2), pyruvate dehydrogenase (PDH), and phosphofructokinase (PFKP) protein levels were also measured. The activation of the apoptotic pathway was investigated using a confocal microscope, fluorescence- activated cell sorting, and cell three-dimensional imaging was used. Results: In astrocytes, IS affected glycolysis in not only dose-dependently but also time-dependently. Additionally, HK1, PKM2, PDH, and PFKP levels were decreased in IS-treated group when compared to the control. The results were prominent in cases with higher doses and longer exposure duration. The apoptotic features after IS treatment were also observed. Conclusion: Our results showed that the inhibition of glycolysis by IS in astrocytes leads to cell death via apoptosis. Specifically, longterm and higher-dose exposures had more serious effects on astrocytes. Our results suggest that the glycolysis pathway and related targets could provide a novel approach to cognitive dysfunction in CKD patients.

In Harrison’s Principles of Internal Medicine, human understanding is emphasized as one of three necessary characteristics that a physician must have. Inflammation, which is caused by inflammatory inducers (inf-ids), is a fundamental feature of disease at the cellular and molecular levels. Inflammation protects the body, but excessive or prolonged inflammation can be damaging and can cause disease. Humans are repeatedly exposed to external and internal environmental factors that generate inf-ids throughout their lives. External environmental factors include microbial and non-microbial inf-ids, as well as stressors that inevitably arise during social interactions. Internal environmental factors include the adaptive physiological response that is present from birth. Inf-ids may also be produced by the four-step habit loop, which consists of a cue (e.g., stressor), emotions, routine act (adaptive response), and a reward. Immune cells in the circulatory system and in tissues may have positive and negative effects in inflammatory responses. However, low-grade inflammation may be difficult to detect. We propose a model of disease development that integrates external and internal environmental factors from the perspective of human understanding.