Activation of AMPK-PGC-1α pathway ameliorates peritoneal dialysis related peritoneal fibrosis in mice by enhancing mitochondrial biogenesis

Abstract

Background The pathogenesis of peritoneal dialysis (PD)-related peritoneal fibrosis (PF) is not clearly understood, and current treatment options are limited. Methods In this study, the effect of PD-related PF on mitochondrial biogenesis was investigated, and the effect of activation of the adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway on PF was evaluated in mice. Results In a mouse model of PD-related PF, AMPK-PGC-1α signaling (phospho-AMPK, PGC-1α, NRF-1, NRF-2 and TFAM expression) was downregulated, mitochondrial DNA (mtDNA) levels were reduced, and mitochondrial structure was damaged in the peritoneum. In addition, TdT-mediated dUTP nick-end labeling (TUNEL) staining showed typical apoptosis characteristics in peritoneal mesothelial cells (PMCs). Activation of the AMPK-PGC-1α pathway (PGC-1α overexpression or metformin, which is an agonist of AMPK) upregulated phospho-AMPK, PGC-1α, nuclear respiratory factors 1 (NRF-1) and 2 (NRF-2), and mitochondrial transcription factor A (TFAM) expression and mtDNA content, improved mitochondrial morphological manifestations, inhibited apoptosis of PMCs and alleviated PF. Conclusion Our study may suggest that activation of the AMPK-PGC-1α pathway ameliorates PD-related PF by enhancing mitochondrial biogenesis.

Activation of PGC‐1α‐dependent mitochondrial biogenesis supports therapeutic effects of silibinin against type I diabetic periodontitis

“…Compared with the D group, the DP group had a lower mtDNA copy number, which was increased by silibinin (Figure 2e). Mitochondrial biogenesis is regulated by the PGC‐1α‐mitochondrial transcription factor A (TFAM)–nuclear respiratory factor‐2 (NRF2)–nuclear respiratory factor‐1 (NRF1) pathway (Wu et al, 2022). We found that PGC‐1α, TFAM and NRF2 were significantly down‐regulated at the transcriptional level in the DP group compared with the D group.…”

Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis

“…In human peritoneal MCs, high glucose PDF induced excessive ROS production and lipid peroxidation with oxidative DNA damage [ 197 ]. In mice, PDF exposure downregulated the adenine monophosphate (AMP) activated protein kinase (AMPK)- peroxisome proliferator activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathway, including decreased expression of p-AMPK, PGC-1α, nuclear factor-erythroid 2-related factor (NRF)-1, NRF-2, and the mitochondrial transcription factor A (TFAM), as well as reduced levels of mitochondrial DNA and damaged mitochondrial structure in the peritoneum [ 198 ]. In this model, treatment with metformin, an AMPK agonist, improved all these parameters and inhibited apoptosis of peritoneal MCs with the consequent improvement of peritoneal fibrosis [ 198 ].…”

“…In mice, PDF exposure downregulated the adenine monophosphate (AMP) activated protein kinase (AMPK)- peroxisome proliferator activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathway, including decreased expression of p-AMPK, PGC-1α, nuclear factor-erythroid 2-related factor (NRF)-1, NRF-2, and the mitochondrial transcription factor A (TFAM), as well as reduced levels of mitochondrial DNA and damaged mitochondrial structure in the peritoneum [ 198 ]. In this model, treatment with metformin, an AMPK agonist, improved all these parameters and inhibited apoptosis of peritoneal MCs with the consequent improvement of peritoneal fibrosis [ 198 ]. Moreover, mitochonic acid-5 (MA-5), an indole-3-acetic acid derivative, has been shown to improve mitochondrial dysfunction and peritoneal damage in a model of peritoneal fibrosis induced by CG [ 199 ].…”

Mechanisms and effects of metformin on skeletal muscle disorders

“…The levels of PGC-1α, NRF-1, NRF-2, and TFAM proteins were reduced in a mouse model of peritoneal fibrosis associated with peritoneal dialysis, indicating significant inhibition of mitochondrial biosynthesis. Metformin may partially act on the AMPK/PGC-1α pathway to increase mitochondrial DNA content, improve mitochondrial morphology, and enhance mitochondrial biosynthesis to reduce peritoneal dialysis related peritoneal fibrosis in mice ( 91 ).…”