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Functional mechanism of AMPK activation in mitochondrial regeneration of rat peritoneal macrophages mediated by uremic serum.

ABSTRACT: OBJECTIVE:To investigate the effects of AMPK activation on mitochondrial inhibition by uremic serum through the AMPK-activated rat peritoneal macrophages stimulated by uremic serum, thereby providing a reference for the clinical treatment of chronic kidney disease. METHODS:Twenty-two male Sprague-Dawley (SD) rats were included as experimental subjects. Fifteen rats were constructed into chronic kidney disease models (the model group). The remaining seven rats only received renal capsule stripping instead of nephrectomy (the sham-operated group). Ten weeks after model construction, the bodyweight, blood biochemical indicators, and metabolic parameters of rats in groups were measured. Meanwhile, the expression of the M1 phenotype marker protein in peritoneal macrophages was determined. RESULTS:Ten weeks after model construction, the bodyweight of rats in the model group was significantly lower than that in the sham-operated group. The values of urea nitrogen and serum creatinine were significantly higher than those in the sham-operated group (P<0.01). The levels of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), and the monocyte chemoattractant protein 1 (MCP-1) of rats in the model group were significantly higher than those in the sham-operated group (P <0.01). After the lipopolysaccharide (LPS) stimulation, the expressions of M1 phenotype marker mRNA in the model group was significantly increased. The expression of mitochondrial structural protein mRNA in the peritoneal macrophages of rats in the model group was significantly lower than that in the sham-operated group. The expression of M1 phenotype marker mRNA was significantly decreased in the uremic serum group after AMPK agonist (P<0.01). CONCLUSION:In rats with chronic renal insufficiency, mitochondrial regeneration was dysfunctional in macrophages. By activating AMPK, the inhibitory effect of uremia serum on mitochondrial regeneration of macrophages was improved. Therefore, AMPK was a critical factor that could regulate mitochondrial regeneration of macrophages.

SUBMITTER: Chen

PROVIDER: S-EPMC7521755 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Functional mechanism of AMPK activation in mitochondrial regeneration of rat peritoneal macrophages mediated by uremic serum.

Chen De Zuo Kun K Liang Xuan X Wang Mei M Zhang Honghong H Zhou Rong R Liu Xiaoli X

PloS one 20200928 9

PMID: 32986718

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Project description:BackgroundDNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the alpha subunit of AMP-activated protein kinase (AMPK), which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage.Methodology/principal findingsThree pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1alpha and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK alpha subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue) stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway.Conclusions/significanceThese results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM-dependent mitochondrial biogenesis may play a role in DNA damage response and ROS regulation, and that defect in ATM-dependent mitochondrial biogenesis could contribute to the manifestations of A-T disease.

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Functional mechanism of AMPK activation in mitochondrial regeneration of rat peritoneal macrophages mediated by uremic serum.

Publications

Functional mechanism of AMPK activation in mitochondrial regeneration of rat peritoneal macrophages mediated by uremic serum.

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