Abstract
Purpose :
Peroxisome proliferator-activated receptors (PPARs) function as transcription factors that regulate the expression of genes linked to various physiological and pathologic processes. In some ocular diseases, PPARs may play a role in inflammation and angiogenesis. However, their impact on retinitis pigmentosa (RP) remains unclear. This study tested the hypothesis that PPAR regulation can rescue photoreceptors in the rd1 mouse model.
Methods :
Organotypic retinal explants were derived from rd1 mice and cultured with PPAR agonists. After histological workup, cell death in the retina was examined using the TUNEL assay. The activities of poly-ADP-ribose-polymerase (PARP) and calpain-type proteases were assessed using specific assays. One-way analysis of variance (ANOVA) test was used for statistical analysis.
Results :
PPARα and PPARγ agonist treatment significantly reduced rd1 outer nuclear layer (ONL) cell death to 3.84 % (± 0.37, n = 9, p < 0.001) and 3.68 % (± 0.54, n = 12, p < 0.0001) respectively, when compared with untreated rd1 retina (5.07 % ± 0.38, n = 16). In comparison, PPARδ agonist did not affect ONL cell death (4.30 % ± 0.60, n = 10, p > 0.05). We obtained similar results by verifying other photoreceptor degeneration markers, PARP, and its product poly-ADP-ribose (PAR). Treatment with PPARα or PPARγ significantly reduced both PARP activity (PPARα: 2.47 % ± 0.45, n = 8, p < 0.01; PPARγ: 2.40 % ± 0.35, n = 6, p < 0.01) and PAR generation (PPARα: 1.04 % ± 0.27, n = 10, p < 0.001; PPARγ: 1.20 % ± 0.14, n = 6, p < 0.01) in rd1 ONL, when compared with untreated rd1 retina (PARP: 3.22 % ± 0.12, n = 8; PAR: 1.73 % ± 0.45, n = 8). Calpain has been connected to the pathogenesis of RP. Calpain activity and calpain-2 activation were high in rd1 retina (calpain activity: 3.34 % ± 0.46, n = 16; calpain-2: 4.68 % ± 0.50, n = 9). PPARγ significantly reduced both overall calpain activity and calpain-2 activation to 2.29 % (± 0.44, n = 5, p < 0.001) and 2.62 % (± 0.56, n = 5, p < 0.0001).
Conclusions :
Our results indicate that PPAR may be beneficial for rd1 photoreceptors since activation of PPARα and PPARγ increased photoreceptor viability. Notably, PPARγ may rescue photoreceptors by regulating calpain activity. This study contributes to our understanding of degenerative mechanisms in RP and may provide new targets for therapeutic intervention.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.