BDNF Overexpression in Bladder Induces Neuronal Changes To Mediate Bladder Overactivity

Elevated levels of brain derived neurotrophic factor (BDNF) in urine of overactive bladder (OAB) patients support the association of BDNF with OAB symptoms, but the causality is not known. Here, we investigated the functionality of BDNF overexpression in rat bladder following bladder wall transfection of either BDNF or luciferase transgenes (10µg). A week after transfection, BDNF overexpression in bladder tissue and elevation of urine BDNF levels was observed together with increased transcript of BDNF, its cognate receptors (TrkB & p75NTR) and downstream PLCγ isoforms in bladder. BDNF overexpression can induce the bladder overactivity (BO) phenotype is demonstrated by the increased voiding pressure and reduced intercontractile interval during transurethral open cystometry under urethane anesthesia. A role for BDNF mediated enhancement of pre-junctional cholinergic transmission in BO is supported by the significant increase in the atropine and neostigmine sensitive component of nerve-evoked contractions and upregulation of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), transporter Oct2 and α1 receptors. In addition, higher expression of transient receptor channels (TRPV1 and TRPA1) and pannexin-1 channels in conjunction with elevation of ATP and neurotrophins in bladder and in L6/S1 dorsal root ganglia together support a role for sensitized afferent nerve terminals in BO. Overall, genomic changes in efferent and afferent neurons of bladder induced by the overexpression of BDNF per se establishes a mechanistic link between elevated BDNF levels in urine and dysfunctional voiding observed in animal models and in OAB patients.

American journal of physiology. Renal physiology. 2017 Nov 01 [Epub ahead of print]

Mahendra Kashyap, Subrata Pore, William C de Groat, Christopher Chermansky, Naoki Yoshimura, Pradeep Tyagi

University of Pittsburgh., University of Pittsburgh .