Journal Article

The Protective Role of PGC‐1α in Cystitis Glandularis: Mitigating Mitochondrial Injury and Inflammation

Zhong, Wei, Fu, Yue, Hu, Haiwei, Ge, Bo, Tang, Yongbo, Su, Jimin, Chen, Min, Cui, Ende, Wen, Zhouliang

2024

Overview

Background: Peroxisome proliferator‐activated receptor‐gamma coactivator‐1α (PGC‐1α), a regulator of mitochondrial function, plays a critical role in inflammation and may be involved in cystitis glandularis (CG) development. Methods: LPS was administered to establish a CG model in female Sprague–Dawley (SD) rats and to induce cellular injury in the human urothelial cell line SV‐HUC‐1. Subsequently, to elucidate the role of PGC‐1α signaling in CG, both the animal and cellular models were treated with ZLN005, a specific activator of PGC‐1α. Cell viability was assessed using the cell‐counting kit‐8 (CCK8) assay. Mitochondrial damage was quantified by measuring reactive oxygen species (ROS), assessing mitochondrial membrane potential, and examining mitochondrial ultrastructure via transmission electron microscopy (TEM). Enzyme‐linked immunosorbent assays (ELISA) were utilized to determine the levels of inflammatory cytokines, namely, IL‐1β, IL‐6, and TNF‐α. Furthermore, the protein expression of silent information regulation 1 (SIRT1), PGC‐1α, mitochondrial transcription factor A (TFAM), nuclear respiratory factor 1 (NRF1), and nuclear respiratory factor 2 (NRF2) was evaluated using immunohistochemistry and/or Western blot analysis. Results: LPS‐treated rat bladder exhibited histological characteristics of CG, including increased urothelial proliferation and inflammation. PGC‐1α protein levels were downregulated in human CG tissues, LPS‐treated rat bladders, and SV‐HUC‐1 cells. Mitochondrial damage was observed in both rat CG and LPS‐irritated cells with elevated ROS and diminished mitochondrial membrane potential. TEM documented mitochondrial morphological injury of the urothelium in rat CG. ZLN005 attenuated LPS‐induced epithelial hyperplasia and inflammatory cytokine secretion in the rat CG model. Furthermore, ZLN005 partially reversed LPS‐induced mitochondrial damage, as indicated by reduced ROS levels, restored mitochondrial membrane potential, and mitigated mitochondrial morphological injury in both rat CG and LPS‐stimulated cells. In addition, ZLN005 restored the expression of PGC‐1α and its associated signaling proteins SIRT1, TFAM, NRF1, and NRF2. Conclusions: The downregulation of PGC‐1α suggests its potential as a molecular marker for the progression of CG. Targeting the PGC‐1α signaling pathway may offer an effective therapeutic intervention for the clinical management of CG.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Animal models / Biopsy / Biosynthesis / Bladder / Cell culture / Cell proliferation / Cell viability / Cystitis / Down-regulation / Enzyme-linked immunosorbent assay / Females / GA-binding protein / Hyperplasia / Immunohistochemistry / Inflammation / Kidneys / Lipopolysaccharides / Membrane potential / Metabolism / Mitochondria / Oxidative stress / Peroxisome proliferator-activated receptors / Reactive oxygen species / Signal transduction / SIRT1 protein / Transmission electron microscopy / Tumor necrosis factor-α / Ultrastructure / Urogenital system / Urothelium