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Ursodeoxycholic acid ameliorates erectile dysfunction and corporal fibrosis in diabetic rats by inhibiting the TGF-β1/Smad2 pathway

International Journal of Impotence Research (2024)Cite this article

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Abstract

Corporal tissue fibrosis is critical in diabetes-associated erectile dysfunction. Transforming growth factor-β1/Small mothers against decapentaplegic-2 (TGF-β1/Smad2) contributes to the induction of fibrosis in corporal tissue. Smad7 is accepted as a general negative regulator of Smad signaling, although its role in corporal fibrosis is unknown. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid used for biliary and liver related disorders and has antifibrotic effects in the liver. This study investigated the effects of UDCA on diabetic erectile dysfunction. Forty-eight male Spraque Dawley rats were divided into six groups: nondiabetic (n = 6), nondiabetic+20 mg/kg UDCA (n = 6), nondiabetic+80 mg/kg UDCA (n = 6), diabetic (n = 10), diabetic+20 mg/kg UDCA (n = 10), diabetic+80 mg/kg UDCA (n = 10). Diabetes was induced by intraperitoneal injection of 60 mg/kg Streptozocin. UDCA (20 and 80 mg/kg/day) or saline was subsequently administered via oral gavage for 56 days. Erectile function was evaluated as measurement of maximum intracavernosal pressure (m-ICP)/mean arterial pressure (MAP) and total ICP/MAP. Corporal tissues were evaluated by Western blotting and Masson’s trichrome staining. Electrical stimulation-induced m-ICP/MAP responses were higher in UDCA-treated diabetic rats compared to untreated diabetic rats, respectively (20 mg/kg; 4 V: 0.77 ± 0.11 vs 0.45 ± 0.09, p = 0.0001 and 80 mg/kg; 4 V: 0.78 ± 0.11 vs 0.45 ± 0.09, p = 0.0001) UDCA prevented the increase in phospho-Smad2 and fibronectin protein expressions in diabetic corporal tissue both at 20 mg/kg (p = 0.0002, p = 0.002 respectively) and 80 mg/kg doses (p < 0.0001 for both). Smad7 protein expressions were significantly increased in the UDCA-treated diabetic groups compared to the untreated diabetic group (20 mg/kg: p = 0.0079; 80 mg/kg: p = 0.004). Furthermore, UDCA significantly prevented diabetes-induced increase in collagen (20 mg/kg: p = 0.0172; 80 mg/kg: p = 0.0003) and smooth muscle loss (20 mg/kg: p = 0.044; 80 mg/kg: p = 0.039). In conclusion, UDCA has a potential protective effect on erectile function in diabetic rats by altering fibrotic pathways via inhibition of TGF-β1/Smad2 and activation of Smad7.

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Fig. 1: Experimental design. Rats received an i.p. injection of STZ or vehicle.
Fig. 2: Representative ICP (green) and MAP (red) tracings were measured through stimulation of 8 V for 1 min (scale interval 60 s).
Fig. 3: Treatment of UDCA augmented erectile function elicited by electrical stimulation.
Fig. 4: Treatment of UDCA augmented erectile function elicited by electrical stimulation.
Fig. 5: The levels of pSmad2, pSmad2/Smad2, Smad7 and fibronectin protein expression in corpus cavernosum of ND, D and ND + UDCA (20 mg/kg and 80 mg/kg, respectively).
Fig. 6: Histological changes in the rat corpus cavernosum mediated by UDCA.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to acknowledge Feride Sena Sezen’s contribution to the experimental methodology, Yesim Kaya Yasar’s contribution to the analysis of the data, Atlas Biotechnology Laboratory’s (Ankara, Türkiye) contribution to the analysis of Western Blot, Scientific Research Project Coordination Unit of Karadeniz Technical University for funding and KTU Academic Writing Center for checking the English linguistics of the article.

Funding

This study was supported by the Scientific Research Project Coordination Unit of Karadeniz Technical University (Grant Number: TDK-2020-8748) and presented as a part of doctoral thesis.

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  1. Department of Pharmacology, Graduate School of Health Sciences, Karadeniz Technical University, Trabzon, Türkiye

    Irem Cavusoglu Nalbantoglu

  2. Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye

    Serhat Sevgi

  3. Department of Histology and Embryology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye

    Gokcen Kerimoglu

  4. Department of Pharmacology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye

    Mine Kadıoglu Duman & Nuri Ihsan Kalyoncu

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Contributions

Conceptualization: ICN, NIK. Methodology: ICN, SS, GK, NIK. Data curation, investigaton: ICN, SS, GK, MKD, NIK. Funding acquisition: NIK. Writing original draft: ICN, NIK. Review & editing: ICN, SS, MKD, NIK.

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Cavusoglu Nalbantoglu, I., Sevgi, S., Kerimoglu, G. et al. Ursodeoxycholic acid ameliorates erectile dysfunction and corporal fibrosis in diabetic rats by inhibiting the TGF-β1/Smad2 pathway. Int J Impot Res (2024). https://doi.org/10.1038/s41443-024-00868-9

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  • DOI: https://doi.org/10.1038/s41443-024-00868-9

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