Abstract
INTRODUCTION AND OBJECTIVE: The clinical relevance of the ratio NGF/creatinine in urine as a biomarker for overactive bladder syndrome (OAB) diagnosis is a matter of debate. ProNGF, the precursor form of nerve growth factor (NGF) was recently found to possess degenerative roles by signalling through its receptor p75NTR. The present study aims to identify the changes in concentration of NGF and proNGF, and the soluble factors involved in their proteolysis in the urine of an aging female population with OAB. METHODS: Urine samples were obtained from 20 females of 50-80 years of age with OAB and from 20 controls of the same age group. Analyses were carried out with highly specific ELISA and enzymatic kits. Participants completed a full clinical evaluation and validated self-reported questionnaires of lower urinary tract symptoms as well as a one-day voiding diary. RESULTS: NGF ELISA kit specificity was confirmed. ProNGF/NGF ratio was significantly increased in the urine of OAB subjects. Enzymatic activities of plasmin and matrix metalloproteinase 7 (MMP-7), the main enzymes responsible for extracellular processing of proNGF to NGF, were similar between controls and OAB when normalized to their respective inhibitors, α2-antiplasmin inhibitor and TIMP-1. On the other hand, metalloproteinase 9 (MMP-9), the enzyme responsible for the proteolysis of NGF into peptides, displayed a marked increased activity even when normalized to its inhibitor TIMP-1. On the other hand, nitric oxide and PGE2, two factors increasing expression and activity of MMP-9, also displayed higher concentrations in urine of OAB patients. CONCLUSIONS: The ratio ProNGF/NGF could constitute a more reliable biomarker for OAB rather than NGF level alone. This increase could originate from MMP-9 overactivity enhancing NGF proteolysis in OAB. This suggests that MMP9 inhibitors could constitute a new therapeutic target to treat OAB patients. Source of Funding: Urology Care Foundation Rising Star in Urology Research Award and the Quebec Network for Research on Aging
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