Differential heat shock protein transcript expression in mouse lower urinary tract (LUT) pathways in cyclophosphamide...

Chronic bladder inflammation and psychological stress are key contributors to lower urinary tract dysfunction and pelvic pain, yet the molecular stress responses engaged across bladder tissues and associated neural pathways remain poorly defined. Heat shock proteins (HSPs), critical regulators of cellular stress adaptation, may differentially respond to peripheral injury versus psychogenic stress. Using cyclophosphamide (CYP)-induced cystitis of varying duration, acute stress and repeated variate stress (RVS) paradigms in mice, we examined time-, tissue-, and segment-specific regulation of Hsp60, Hsp70, and Hsp90 transcripts across the urothelium, detrusor, dorsal root ganglia (DRG), and lumbosacral spinal cord. CYP-induced cystitis elicited a rapid, transient induction of all three Hsps examined in the urothelium and detrusor at 4 h, followed by normalization with longer duration of CYP-induced cystitis. In contrast, sensory (DRG) and central (spinal cord) responses were highly structured: sacral (S1) DRG showed early Hsp induction, whereas lumbar DRG and spinal cord segments exhibited delayed suppression of select Hsps during chronic cystitis. Psychogenic stress produced fundamentally different patterns. Longer duration RVS (2w, 4w), but not acute stress, caused progressive and sustained suppression of Hsp expression in the bladder, with earlier onset in the urothelium than detrusor. In contrast, longer duration RVS increased Hsp expression in select DRG and spinal cord segments, particularly L2, L6 DRG and L1, S1 spinal cord, with biphasic regulation. Together, these findings demonstrate that inflammatory and psychogenic stressors engage distinct, tissue-specific heat shock responses across bladder-neural pathways, revealing differential molecular responses that may underlie bladder dysfunction and pelvic pain.