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

Abstract

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.