Long-term diabetes causes molecular alterations related to fibrosis and apoptosis in rat urinary bladder.

Abstract Diabetes induces time-dependent alterations in urinary bladders. Long-term diabetes causes an underactive bladder. However, the fundamental mechanisms are still elusive. This study aimed to examine the histological changes and the potential molecular pathways affected by long-term diabetes in the rat bladder. Diabetes was induced in 8-week-old male Lewis rats by streptozotocin, while age-matched control rats received citrate buffer only. Forty-four weeks after diabetes induction, bladders were harvested for histological and molecular analyses. The expressions of proteins related to fibrosis, apoptosis and oxidative stress as well as the cellular signaling pathway in the bladder were examined by immunoblotting. Histological examinations illustrated diabetes caused detrusor hypertrophy and fibrotic changes in the bladder. Immunoblotting analysis demonstrated higher collagen I but lower elastin expression in the bladder in diabetic rats. These were accompanied by an increase in the expression of transforming growth factor-beta1, along with the downregulation of matrix metalloptoteinase-1, and upregulation of tissue inhibitor of metalloproteinase-1. Diabetic rats showed an increase in nitrotyrosine, but decrease in nuclear factor erythroid-related factor 2 (Nrf2) levels in the bladder. Enhanced apoptotic signaling was observed, characterized by increased expression of Bcl-2-associated X protein (Bax), decreased expression of Bcl-2, in the diabetic bladder. The nerve growth factor level was decreased in the diabetic bladder. A significant suppression in the protein expressions of phosphorylated extracellular signal-regulated kinases 1/2 was found in diabetic bladders. This study demonstrated that long-term diabetes caused molecular changes that could promote fibrosis and apoptosis in the bladder. Oxidative stress may be involved in this context.