Curcumin improves bladder dysfunction in diabetic rats by attenuating oxidative stress via the Keap1/NRF2/HO-1 pathway

Introduction

Diabetic bladder dysfunction (DBD) is a prevalent urological complication in individuals with diabetes mellitus (DM), affecting more than half of them (1). Its main symptoms include abnormal bladder sensation, detrusor overactivity, and difficulty urinating (2). Currently, there are no effective disease-modifying treatments specifically for DBD, with management primarily focused on symptomatic relief.

Hyperglycemia-induced oxidative stress (OS) plays a significant role in the onset and progression of DBD (3). It damages bladder smooth muscle cells (BSMC), induces apoptosis in these cells, and impairs the release of neurotrophic factors, leading to neuronal dysfunction. These pathological changes ultimately result in bladder sensory abnormalities, thereby driving DBD development (3-6).

Curcumin (Cur), a polyphenolic compound derived from turmeric, exhibits a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, and anti-fibrotic effects (7,8). For instance, it ameliorates OS and inhibits apoptosis in diabetic cardiomyocytes via the PI3K/AKT pathway (9). In addition, it can alleviate OS through the GSK-3β/NRF2 signaling pathway for the treatment and prevention of osteoporosis (10). Furthermore, Cur enhances hepatic antioxidant capacity and ameliorates alcoholic liver injury in rats (11). Collectively, these studies demonstrate that Cur enhances cellular antioxidant capacity and mitigates OS, highlighting its significant potential in treating OS-related diseases. However, its effects on DBD remain unexplored. Therefore, this study aims to investigate these effects and explore Cur’s therapeutic potential for DBD. We present this article in accordance with the ARRIVE and MDAR reporting checklists (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0107/rc).

Methods

Cell culture and grouping

The BSMC used in this study were sourced from Zhejiang Meisen Cell Technology (Jinhua, China) and cultured in DMEM (Gibco, Waltham, USA) supplemented with 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Solarbio, Beijing, China) at 37 ℃ under 5% CO₂. Cells were divided into four groups: the control group, the Cur group, the high glucose (HG) group and the HG + Cur group. The Cur group and the HG + Cur group were treated with 5 µM Cur (Solarbio) for 24 h, while the control group and the HG groups received an equal volume of phosphate-buffered saline (PBS). Subsequently, to mimic diabetic conditions, cells in the HG and HG + Cur groups were cultured in HG DMEM (30 mM) for 24 h. The control group and the Cur group were still cultured in normal DMEM.

Assessment of cell viability

Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay (Beyotime, Shanghai, China). Briefly, BSMC were seeded in a 96-well plate. After the treatment period, 10 µL of CCK-8 reagent was added to each well, followed by incubation at 37 ℃ for 1 h in the dark. Absorbance was then measured at 450 nm.

Reactive oxygen species (ROS) assay

Intracellular ROS levels were measured using a ROS assay kit (Beyotime) following the manufacturer’s instructions. Briefly, cells were stained with DCFH-DA at 37 ℃ in the dark for 20 min, washed, and then analyzed by flow cytometry (FCM).

Western blot (WB) analysis

BSMC and bladder tissues were lysed on ice for 30 min using radioimmunoprecipitation assay lysis buffer (Solarbio) supplemented with protease and phosphatase inhibitors (Solarbio). After centrifugation at 12,000 ×g for 15 min at 4 ℃, the supernatant was collected, and protein concentration was determined using a BCA assay kit (Thermo Fisher Scientific, Waltham, USA). Equal amounts of protein were separated by SDS-PAGE and transferred onto polyvinylidene difluoride membranes (Millipore, Burlington, USA). The membranes were blocked with 5% non-fat milk for 1 h at room temperature and then incubated overnight at 4 ℃ with the following primary antibodies including β-actin (Proteintech, Wuhan, China), kelch-like ECH-associated protein 1 (Keap1, Proteintech), nuclear factor erythroid 2-related factor 2 (NRF2, Proteintech), heme oxygenase-1 (HO-1, Proteintech), Superoxide Dismutase 1 (SOD1, Proteintech), B-cell lymphoma 2 (BCL-2, ABclonal, Wuhan, China), BCL-2-associated X protein (BAX, Servivebio, Wuhan, China), cysteine-aspartic acid protease 3 (Caspase-3, ABclonal). The next day, the membranes were washed three times with Tris-buffered saline containing 0.1% Tween 20 for 10 min each and incubated with a horseradish peroxidase-linked secondary antibody for 1 h at room temperature. The membranes were washed three times again. The protein bands were visualized utilizing the Fujifilm LAS-4000 Image Analyzer (Japan). Finally, captured protein bands were analyzed using ImageJ software (USA).

Immunofluorescence (IF)

The BSMC were fixed with 4% paraformaldehyde (Servivebio), permeabilized with 0.1% Triton X-100 (Solarbio), and blocked with 5% bovine serum albumin for 1 h at room temperature. Subsequently, the BSMC were incubated overnight at 4 ℃ with against NRF2 (Proteintech). The next day, the BSMC were washed three times with PBS, followed by incubation with corresponding secondary antibodies. Cell nuclei were counterstained with DAPI for 5 min. A secondary-only control was included as a negative control, and no significant signal was observed. Fluorescence images were captured using a fluorescence microscope.

Assessment of cell apoptosis

Cell apoptosis was assessed by FCM using an Annexin V-FITC/PI kit (Keygen Biotech, Nanjing, China) according to the manufacturer’s protocol. Briefly, the cells were harvested and washed twice with PBS (centrifuged at 300 ×g for 5 min). The cells were then resuspended in 500 µL of binding buffer, followed by the addition of 5 µL of Annexin V-FITC and 5 µL of propidium iodide. The mixture was incubated at room temperature in the dark for 10 min before detection.

Animals

All animal experiments were approved by the Animal Care and Use Committee of Shandong University (No. 2025-087), and conducted in accordance with the national and institutional guidelines for the care and use of animals. Male Sprague-Dawley rats (n=45, aged 4 weeks) were obtained from Jinan Pengyue Laboratory Animal Breeding Co., Ltd. (Jinan, China). All rats were maintained in a temperature-controlled environment of 22–24 ℃ with a 12 h light/dark cycle and free access to food and water. The rats were randomly divided into a control group (n=15) fed a standard chow diet, and a diabetes induction group (n=30) fed a high-fat diet. After 4 weeks, diabetes was induced in the induction group via a single intraperitoneal injection of streptozotocin (65 mg/kg, Solarbio) dissolved in sodium citrate buffer. The control group received an equal volume of the buffer. The diabetic model was considered successful if the fasting blood glucose level measured, 72 h post-injection, exceeded 16.7 mmol/L. Based on this criterion, diabetes was successfully induced in 28 rats. These diabetic rats were randomly allocated into two groups (n=14 per group), the DM group and the DM-Cur group. All rats received daily gavages for 6 weeks. The DM-Cur group received Cur (75 mg/kg) (9,12) and both the Control and DM groups received an equal volume of PBS. During the treatment period, 3 rats in the DM group and 2 in the DM-Cur group died.

Urodynamic experiment

Rats were anesthetized with urethane (1.5 g/kg) and placed in a supine position. Rats were anesthetized with urethane (1.5 g/kg) and placed in a supine position. A midline abdominal incision was made, and a PE-10 tube was inserted into the bladder through the dome. Saline solution (37 ℃) was then infused at a rate of 0.06 mL/min, and bladder contractions were measured using a data acquisition system (LabChart 8, AD). After the start of the experiment, a 0.5 h stabilization period was allowed, followed by 1 h recording of intravesical pressure. The contraction intervals, pressure threshold for initiating voiding, and peak voiding pressure were recorded.

Histological test

Bladder tissues were fixed in 4% paraformaldehyde, embedded in paraffin, and sectioned. Masson’s trichrome staining was performed to quantify the smooth muscle-to-collagen ratio. Images were acquired using a NanoZoomer S60 scanner and analyzed with ImageJ software. For each section, three areas were selected for analysis. Apoptosis was assessed using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Images were acquired using a NanoZoomer S60 scanner. For each section, three areas were selected for analysis, and the ratio of apoptotic cells to total cells was calculated.

Statistical analysis

Statistical analyses were performed using GraphPad Prism (version 8.0, USA). All experiments were repeated three times. All data were presented as mean ± standard error of the mean (SEM). All data were normally distributed, and one-way ANOVA was used to assess differences between groups. P<0.05 was considered statistically significant.

Results

Cur inhibited HG-induced BSMC injury

To evaluate the effect of Cur on cell viability, the survival rate of BSMC under different treatments was assessed using the CCK-8 assay. As shown in Figure 1A, an appropriate concentration of Cur promoted BSMC proliferation, whereas excessive Cur inhibited cell growth. The results indicated that the optimal pro‑proliferative effect was observed at a Cur concentration of 5 µmol/L. Therefore, this concentration was selected for Cur treatment in subsequent experiments. HG treatment decreased the viability of BSMC. The addition of Cur alleviated this HG-induced damage (Figure 1B).

Figure 1 Cell viability and ROS detection. (A) Cell viability after treatment with different concentrations of Cur. (B) Effect of Cur on viability of HG-treated BSMC. (C) Intracellular ROS levels were detected by FCM. (D) Quantitative statistical analysis of ROS levels. n=3. Data are presented as mean ± SD. Statistical analysis was performed using one-way ANOVA. *, P<0.05; ***, P<0.001; ****, P<0.0001. ANOVA, analysis of variance; BSMC, bladder smooth muscle cell; Cur, Curcumin; FCM, flow cytometry; FITC-A, fluorescein isothiocyanate-area; HG, high glucose; ROS, reactive oxygen species; SD, standard deviation.

Cur reduces intracellular ROS levels in HG stimulated BSMC

Intracellular ROS generation was assessed by FCM. As shown in Figure 1C,1D, HG stimulation significantly increased ROS levels in BSMC compared to the control. This HG-induced increase was, however, markedly attenuated by co-treatment with Cur, indicating that Cur effectively reduces intracellular ROS overproduction.

Cur enhances cellular antioxidant capacity through the Keap1/NRF2/HO-1 signaling pathway

NRF2 is a central regulator of the cellular antioxidant response. WB analysis was used to examine its pathway activity (Figure 2). Compared to the control group, HG stimulation upregulated Keap1 while downregulating NRF2 and its downstream effectors, including HO-1 and SOD1, indicating an impaired antioxidant defense. In contrast, Cur treatment reversed these HG-induced alterations. The HG + Cur group exhibited reduced Keap1 alongside elevated levels of NRF2, HO-1, and SOD1 compared to the HG group, reflecting a restoration of antioxidant capacity. Notably, Cur alone also enhanced the NRF2 pathway relative to the Control, further boosting antioxidant activity. Collectively, these results demonstrate that Cur activates the Keap1/NRF2/HO-1 axis to reinforce cellular antioxidant defenses.

Figure 2 Cur enhances cellular antioxidant capacity via the Keap1/NRF2/HO-1 signaling pathway. (A) Statistical analysis of Keap1. (B) Statistical analysis of NRF2. (C) Statistical analysis of HO-1. (D) Statistical analysis of SOD1. (E) IF of NRF2. n=3. Data are presented as mean ± SD. Statistical analysis was performed using one‑way ANOVA. *, P<0.05; **, P<0.01; ***, P<0.001. ANOVA, analysis of variance; Cur, Curcumin; DAPI, 4',6-diamidino-2-phenylindole; HG, high glucose; IF, immunofluorescence; SD, standard deviation.

Cur mitigates HG-induced apoptosis

FCM analysis showed that Cur treatment reduced the proportion of apoptotic cells induced by HG stimulation (Figure 3A,3B). At the molecular level, WB revealed that HG stimulation increased the levels of pro-apoptotic proteins, including BAX and Caspase-3, and decreased the anti-apoptotic protein BCL-2. Correspondingly, in HG + Cur group, co-treatment with Cur downregulated the expression of BAX and Caspase-3 while upregulating BCL-2 compared to the HG group (Figure 3C-3E). These findings collectively confirm that Cur mitigates HG-induced apoptosis.

Figure 3 Cur reduces apoptosis in HG-stimulated BSMC. (A) FCM analysis showing the proportion of apoptotic cells. (B) Quantitation of apoptotic cells from FCM. (C) Statistical analysis of BAX. (D) Statistical analysis of Caspase-3. (E) Statistical analysis of BCL-2. n=3. Data are presented as mean ± SD. Statistical analysis was performed using one‑way ANOVA. *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. ANOVA, analysis of variance; BSMC, bladder smooth muscle cell; Cur, Curcumin; FCM, flow cytometry; HG, high glucose; SD, standard deviation.

Cur improves bladder function in DM rats

Urodynamic evaluation showed that rats in the DM group exhibited a significantly higher maximum voiding pressure and longer micturition intervals than those in the Control group (Figure 4A-4C). Cur treatment ameliorated these abnormalities, as evidenced by lower maximum voiding pressure and shorter micturition intervals in the DM-Cur group compared to the DM group. Consistent with these functional impairments, pathological examination revealed exacerbated bladder tissue fibrosis and increased apoptosis in the DM group (Figure 4D-4G). These adverse morphological changes were markedly attenuated in the DM-Cur group. Collectively, these results indicate that Cur effectively ameliorates DBD.

Figure 4 Cur improves bladder function and reduces tissue fibrosis and apoptosis in diabetic rats. (A) Urodynamic experiment of each groups. (B) Maximum voiding pressure in each group. (C) Micturition interval in each group. (D) The Masson staining (magnification ×200). (E) The bladder TUNEL staining (magnification ×200). (F) The ratio of smooth muscle to collagen. (G) Statistics of apoptotic cells. The Control group n=15, the DM group n=11, the DM-Cur group n=12. Data are presented as mean ± SD. Statistical analysis was performed using one‑way ANOVA. *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001. ANOVA, analysis of variance; Cur, Curcumin; DM, diabetes mellitus; SD, standard deviation; SMC, smooth muscle cell; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

Cur ameliorates DBD via the Keap1/NRF2/HO-1 signaling pathway

To elucidate the mechanism underlying the therapeutic effect of Cur on DBD, WB analysis was performed. In bladder tissue from rats in the DM group, Keap1 was upregulated while NRF2 and its downstream effectors, HO-1 and SOD1, were downregulated, indicating a compromised antioxidant defense (Figure 5). Cur treatment reversed this molecular profile. Compared to the DM group, the DM-Cur group exhibited downregulated Keap1 and upregulated NRF2, HO-1, and SOD1. These findings collectively indicate that Cur alleviates DBD through activation of the Keap1/NRF2/HO-1 pathway.

Figure 5 Cur activates the Keap1/NRF2/HO-1 signaling pathway and enhances antioxidant capacity in diabetic rats. (A) Statistical analysis of Keap1. (B) Statistical analysis of NRF2. (C) Statistical analysis of HO-1. (D) Statistical analysis of SOD1. n=3. Data are presented as mean ± SD. Statistical analysis was performed using one‑way ANOVA. *, P<0.05; **, P<0.01; ***, P<0.001. ANOVA, analysis of variance; Cur, Curcumin; DM, diabetes mellitus; SD, standard deviation.

Discussion

DBD, a common urological complication in diabetic patients, is clinically characterized by storage and voiding symptoms such as dysuria, detrusor overactivity, and increased post-void residual urine, which significantly impair patients’ quality of life (13,14).

DM disrupts cellular metabolism, leading to functional impairment. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a membrane-bound enzyme that contributes to the generation of ROS. It catalyzes the one-electron reduction of oxygen, using NADH or NADPH as electron donors, thereby producing superoxide anions within cells. Under normal physiological conditions, NOX remains in an inactive state. However, hyperglycemia triggers its abnormal activation through mechanisms such as dysregulation of the protein kinase C pathway and the formation of advanced glycation end products. Once activated, hyperactive NOX generates excessive ROS (15,16). Concurrently, excessive NADPH consumption impairs the synthesis of reduced glutathione (GSH) and leads to the accumulation of its oxidized glutathione (GSSG), thereby lowering the GSH/GSSG ratio and further compromising the cell’s antioxidant capacity. Furthermore, hyperglycemia suppresses the activity of antioxidant stress enzymes, thereby reducing the cellular antioxidant defense function (17,18). The combined increase in intracellular ROS production and the decline in cellular ROS clearance capacity collectively lead to severe OS. This state of OS serves as a pivotal driver in the onset and progression of DBD (19-21).

The transcription factor NRF2 acts as a master regulator of the antioxidant response. It binds to the antioxidant response element, thereby activating a suite of cytoprotective genes, such as HO-1, which degrades heme, and SOD1, which neutralizes ROS by converting them into less reactive molecules (17,22,23). Studies in NRF2-knockout diabetic mice demonstrate that NRF2 deficiency exacerbates disease severity, leading to pronounced OS, increased apoptosis, and aggravated DBD symptoms (24). Therefore, these findings solidify NRF2’s status as a key therapeutic target for DBD (21,25,26). Chen et al. and Lin et al. investigated the therapeutic potential of grape seed proanthocyanidin extract and sulforaphane, respectively, in treating DBD by activating the NRF2 signaling pathway (27,28). These studies demonstrated promising therapeutic effects, effectively alleviating DBD in diabetic rat models. While the studies cited above have demonstrated the considerable therapeutic potential of NRF2 activators for DBD, this approach remains underexplored. To expand the therapeutic options for DBD, we were among the first to explore the therapeutic potential of Cur for this condition. Our findings indicate that Cur alleviates DBD by activating the NRF2 pathway, which upregulates downstream antioxidant proteins, diminishes intracellular ROS, and thereby exerts its therapeutic effect. In contrast to other NRF2 activators that primarily exert a singular mechanism of action, Cur offers multiple therapeutic benefits. Beyond activating NRF2, it possesses anti-inflammatory and anti-apoptotic properties and further helps to regulate diabetes-induced lipid metabolism disorders and alleviate insulin resistance (29). Therefore, in treating DBD, Cur may provide broader benefits to the diabetic population, thereby representing a more comprehensive therapeutic strategy.

Cur shows considerable promise for treating DBD. However, several limitations must be addressed before successful clinical translation. A major challenge is its poor aqueous solubility and stability, which severely limit bioavailability. Developing novel formulations to enhance its absorption and delivery is therefore crucial (30). Meanwhile, the optimal dosage of Cur warrants further investigation. As a substance with dual properties of anti-OS and pro-OS, Cur exerts distinct effects on cells depending on its concentration (Figure 1A). Due to its unique molecular structure, Cur can chelate metal ions within cells and undergo a specific Fenton reaction, thereby inducing the occurrence of intracellular OS (31). At an appropriate concentration, Cur induces mild OS that stimulates cells and activates anti-OS signaling pathways, thereby enhancing the cells’ anti-OS capacity. However, when the concentration of Cur is too high, excessive OS exceeds the cellular clearance capacity, leading to the induction of apoptosis (32,33). Regarding safety of Cur, current clinical evidence suggests that Cur is well-tolerated in healthy individuals at daily doses of up to 12 g, with no significant adverse effects reported (12). However, safety profiles appear more complex in populations with underlying comorbidities. For instance, mild gastrointestinal symptoms have been observed in patients with conditions such as cholecystitis or ulcerative colitis at doses of 8 g per day (34). Furthermore, the existing safety data are largely derived from short-term studies, highlighting the need for more long-term clinical trial evidence. In conclusion, while Cur is a low-cost compound with a favorable safety profile and strong therapeutic potential, further research, particularly on advanced formulations and long-term safety, is essential to develop it into a reliable therapy for DBD.

Conclusions

In conclusion, our study demonstrates that Cur regulates OS through the Keap1/NRF2/HO-1 signaling pathway, reduces voiding pressure, prolongs the intercontraction interval and improves bladder function in diabetic rats.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the ARRIVE and MDAR reporting checklists. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0107/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0107/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0107/prf

Funding: This study was supported by Shandong Provincial Natural Science Foundation (No. ZR2024MH014) and National Natural Science Foundation of China (No. 82070782).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0107/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All animal experiments were performed under a project license (No. 2025-087) granted by the Animal Care and Use Committee of Shandong University, in compliance with the national and institutional guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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