N-acetylcysteine partially attenuates oxidative-inflammatory remodeling associated with high-fat-diet-associated bladder dysfunction

Abstract Background To investigate oxidative and inflammatory remodeling in high-fat-diet-associated bladder dysfunction and to preliminarily assess whether N-acetylcysteine (NAC) modulates these changes. Methods In vitro, high glucose-treated mouse bladder smooth muscle cells (BSMCs) of C57BL/6 N origin were assigned to control, high glucose (HG), HG + NAC, and mannitol osmotic control (HO) groups. The high-glucose model represented one metabolic stimulus rather than the full metabolic syndrome microenvironment. Levels of oxidative stress, inflammation, and fibrosis were quantified via spectrophotometry and Western blotting. In vivo, 40 six-week-old male Sprague–Dawley rats were randomly assigned to four groups ( n = 10 per group). The NC group received a standard diet, whereas the other groups received a high-fat diet. After eight weeks of dietary intervention, the low- and high-concentration NAC groups received NAC in drinking water (300 and 900 mg/L, respectively) for four weeks. Blood and bladder tissues were collected at 18 weeks of age. Bladder function was assessed using ex vivo detrusor strips; in vivo urodynamic testing was not performed. Results High glucose increased the measured ROS species, MDA, NLRP3 protein abundance, and the p-NFκB/NFκB ratio, while lowering antioxidant indices in BSMCs. Relative to HG, NAC reduced MDA and NLRP3 abundance and the p-NFκB/NFκB ratio, while increasing CAT, SOD, and GSH-Px indices. Qualitative TEM images suggested mitochondrial morphological alterations with high glucose and partial attenuation with NAC. In vivo, relative to NC, the high-fat-diet group (MS) showed reduced ex vivo detrusor contractile force and increased spontaneous contraction frequency. LNAC partially improved force relative to MS, whereas HNAC did not; force in both NAC-treated groups remained below NC. LNAC frequency remained above NC, while HNAC frequency was lower than MS. Conclusion Together, the cell and animal findings support a working model in which oxidative and inflammatory signaling, including NLRP3/NFκB-related responses, may contribute to high-fat-diet-associated bladder dysfunction and may be modulated by NAC. Both NAC regimens modified selected oxidative and inflammatory-related changes, but functional improvements were incomplete and did not demonstrate a conventional monotonic dose-response relationship.