Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions

• Published in: JCI insight 2020-10, Vol.5 (20)
• Main Authors: Birder, Lori A, Wolf-Johnston, Amanda, Wein, Alan J, Cheng, Fangzhou, Grove-Sullivan, Mara, Kanai, Anthony J, Watson, Alan M, Stoltz, Donna, Watkins, Simon C, Robertson, Anne M, Newman, Diane, Dmochowski, Roger R, Jackson, Edwin K
• Format: Article
• Language: English
• Subjects: Aging; Aging - drug effects; Aging - genetics; Animals; Disease Models, Animal; Female; Guanine - analogs & derivatives; Guanine - pharmacology; Humans; Male; Purine-Nucleoside Phosphorylase - antagonists & inhibitors; Purine-Nucleoside Phosphorylase - genetics; Rats; Urinary Bladder - drug effects; Urinary Bladder - pathology; Urologic Diseases - drug therapy; Urologic Diseases - genetics; Urologic Diseases - pathology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.140109

In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) or vehicle for 6 weeks. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria, and increases in urodamaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural, and physiological abnormalities toward that of a younger state. 8-AG is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uroprotective effects of 8-AG are mediated by increased bladder levels of uroprotective inosine and guanosine and reductions in urodamaging hypoxanthine and xanthine. These findings demonstrate that 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.