This study investigated the mechanism of ABT-263 in the treatment of neurogenic bladder fibrosis (NBF) and its protective effects against upper urinary tract damage (UUTD).

Neurogenic bladder (NB) refers to the dysfunction of lower urinary tract storage and urination due to damage to the central or peripheral nervous system, resulting in a series of lower urinary tract symptoms (LUTS) and complications [1]. So far, there are no good treatments to solve this disease. ABT-263 is a known BH3 mimetic drug which can prevent and reverse the progression of fibrotic diseases and myofibroblast apoptosis. Studies have shown that ABT-263 can alleviate the progression of skin fibrosis, pulmonary fibrosis, biliary fibrosis, and myocardial fibrosis by promoting myofibroblast apoptosis [2]. However, there are no reports on the therapeutic effect of ABT-263 in NBF, especially in severe NBF with UUTD. Therefore, this study explores the function and mechanism of ABT-263 in the treatment of NBF. Sixty 12-week-old SD rats were randomly divided into sham, sham + ABT-263 (50 mg/kg), NBF, NBF + ABT-263 (25 mg/kg, oral gavage), and NBF + ABT-263 (50 mg/kg, oral gavage) groups. After cystometry, bladder and kidney tissue samples were collected for hematoxylin and eosin (HE), Masson, and Sirius red staining, and WB and qPCR detection. Primary rat bladder fibroblasts were isolated, extracted, and cultured. After co-stimulation with TGF-β1 (10 ng/mL) and ABT-263 (concentrations of 0, 0.1, 1, 10, and 100 µmol/L) for 24 h, cells were collected. Cell apoptosis was detected using CCK8, WB, immunofluorescence, and annexin/PI assays.

ABT-263 treatment can alleviate neurogenic hydronephrosis, improved the kidney morphology, reduce bladder fibrosis and improve the bladder function of NBF rats. Compared with the sham group, there was no significant difference in any physical parameters in the sham + ABT-263 (50 mg/kg) group. Compared with the NBF group, most of the markers involved in fibrosis were improved in the NBF + ABT-263 (25 mg/kg) and NBF + ABT-263 (50 mg/kg) groups, while the NBF + ABT-263 (50 mg/kg) group showed a significant improvement. Compared with the TGFβ1 group, when the concentration of ABT-263 increased to 10 umol/L, the cell viability of primary bladder fibroblasts began to decrease, the apoptosis rate increased, the fluorescence intensity of red fluorescent α-SMA decreased, and the protein expression of Cytoc and cleaved caspase-3 began to increase in cell culture.
Meanwhile, when the concentration of ABT-263 was increased to 10 µmol/L, the apoptosis rate of primary bladder fibroblasts increased, and the expression of the anti-apoptotic protein BCL-xL began to decrease.

ABT-263 may promote the apoptosis of bladder fibroblasts through apoptosis pathway and relieve related NBF symptoms.

ABT-263 may plays an important role in relieving alleviating neurogenic bladder fibrosis and protecting bladder and kidney function.

Stein R, Bogaert G, Dogan HS, et al. EAU/ESPU guidelines on the management of neurogenic bladder in children and adolescent part I diagnostics and conservative treatment. Neurourol Urodyn. 2020;39(1):45–57.

Continence 7S1 (2023) 100863
DOI: 10.1016/j.cont.2023.100863