Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury

Shanjie Guo; Danfeng Zhao; Zhenjie Zang; Dingchang Shao; Keqin Zhang; Qiang Fu

doi:10.1093/sexmed/qfad050

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury

Sex Med. 2023 Sep 3;11(4):qfad050. doi: 10.1093/sexmed/qfad050. eCollection 2023 Aug.

Authors

Shanjie Guo¹, Danfeng Zhao^{1

2}, Zhenjie Zang³, Dingchang Shao³, Keqin Zhang^{1

2}, Qiang Fu^{1

2

3

4}

Affiliations

¹ Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
² Engineering Laboratory of Urinary Organ and Functional Reconstruction of Shandong Province, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
³ Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
⁴ Key Laboratory of Urinary Diseases in Universities of Shandong, Shandong First Medical University, Jinan 250021, China.

Abstract

Background: Erectile dysfunction (ED) occurs in an increasing number of patients after radical prostatectomy and cystectomy, and the phenotypic modulation of corpus cavernosum smooth muscle cells is closely related to ED.

Aim: To determine whether endoplasmic reticulum stress (ERS) is implicated in the phenotypic modulation of ED induced by bilateral cavernous nerve injury (BCNI).

Methods: In total, 36 Sprague-Dawley rats were randomly divided into 3 groups: sham, in which rats received sham surgery with bilateral cavernous nerve exposure plus phosphate-buffered saline; control, in which rats received BCNI plus phosphate-buffered saline; and experimental, in which rats received BCNI plus 4-phenylbutyric acid. Analysis of variance and a Bonferroni multiple-comparison test were utilized to evaluate differences among groups.

Outcomes: Erectile function, smooth muscle/collagen ratios, and the expression levels of phenotypic modulation and ERS were measured.

Results: Two ratios-maximum intracavernosal pressure/mean arterial pressure and smooth muscle/collagen-were decreased in the control group as compared with the sham group. In penile tissue, there was increased expression of GRP78 (78-kDa glucose-regulated protein), p-PERK/PERK (phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase), caspase 3, CHOP (C/EBP homologous protein), and OPN (osteopontin) but decreased expression of nNOS (neuronal nitric oxide synthase) and α-SMA (α-smooth muscle actin). As compared with the control group, erectile function was improved and pathologic changes were partially recovered in the experimental group.

Clinical translation: The present study demonstrated that ERS is involved in ED caused by cavernous nerve injury, thereby providing a new target and theoretical basis for clinical treatment.

Strengths and limitations: The present study demonstrated for the first time that ERS is related to ED caused by cavernous nerve injury. Inhibition of ERS reverses phenotypic modulation and improves erectile function in rats with BCNI. Additional in vitro studies should be performed to verify these conclusions and explore the specific mechanism of phenotypic modulation.

Conclusion: The present study demonstrated that inhibiting ERS reverses phenotypic modulation and enhances erectile function in rats with BCNI.

Keywords: cavernous nerve injury; endoplasmic reticulum stress; erectile dysfunction; phenotypic modulation; smooth muscle.