Urinary PNPase activity determines the balance between uro-protective purines (known to exert antioxidant, anti-inflammatory, and tissue-protective effects) and uro-damaging purines (known to be pro-oxidant, pro-inflammatory, and tissue-damaging). Thus, PNPase expression is a pivotal regulatory factor of cellular function where abnormal activity results in a dysregulated purine metabolome, ultimately producing an injurious effect rather than a protective one.
These biochemical effects of PNPase may account for many of the cellular abnormalities associated with IC/BPS. We have previously reported that treating IC/BPS animal models with a purine analog (8-aminoguanine, 8AG) that inhibits the formation of tissue-damaging purines and increases tissue-protective purines reverses IC/BPS-induced bladder dysfunction and pain behavior.3 Thus, dysregulation of PNPase may be a key contributing factor in the initiation (and perhaps the long-lasting maintenance) of pathways resulting in bladder pain.
Here, we show that IC/BPS patients with or without Hunner lesions demonstrate higher levels of urotoxic purine metabolites that produce harmful ROS as compared to healthy controls. Apart from a potential role as a diagnostic biomarker for IC/BPS, our findings suggest pathophysiological commonalities between patient subtypes. Further, the accumulation of neuroprotective purines and depletion of urodamaging purines by PNPase inhibition may be therapeutically effective in both groups of patients. The promise of an effective treatment that would avert the adverse events occurring in IC/BPS patients is extremely enticing.
Written by: Lori Birder, PhD, Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
References:
- Edwin Jackson, Stevan Tofovic, Yuanyuan Chen and Lori Birder. 8-aminopurines: a promising new direction for purine-based therapeutics. Hypertension, 2024.
- Lori A. Birder and Edwin K. Jackson. Perspective: Purine nucleoside phosphorylase as a target to treat age associated LUT dysfunction. Nature Urology Reviews, 19:681-687, 2022.doi:10/1038/s41585-022-00642-w., PMID:36071153.
- Amanda Wolf-Johnston, Youko Ikeda, Irina Zabbarova, Anthony J. Kanai, Sheldon Bastacky, Robert Moldwin, Joel N.H. Stern, Edwin K. Jackson* and Lori A. Birder*. Purine nucleoside phosphorylase inhibition- an effective approach for the treatment of chemical hemorrhagic cystitis. J Clinical Investigation Insight, 2024:e176103. doi:10.1172/jci.insight.176103.