Huang Lin1, Tao Wang1, Yajun Ruan1, Kang Liu1, Hao Li1, Shaogang Wang1, Mingchao Li2, Jihong Liu1. 1. Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. 2. Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Electronic address: chaoren149@163.com.
Abstract
INTRODUCTION: Erectile dysfunction (ED), which is common in patients with diabetes mellitus (DM), seriously affects quality of life. Previous studies on the treatment of DM-induced ED (DMED) involve autophagy, but the specific effect and mechanism of treatment are not yet clear. AIM: To investigate the effect and mechanism of rapamycin, an autophagy inducer, in ameliorating DMED. METHODS: 45 male Sprague-Dawley rats (7 weeks old) were used in the experiment. 8 rats were randomly selected as the control group; the other rats were treated with streptozotocin to induce type 1 DM. After 10 weeks, an apomorphine test was used to confirm DMED. Rats with DMED were intraperitoneally injected with rapamycin or vehicle for 3 weeks. Rats in the control group were injected with saline. Erectile function in rats was measured by electrically stimulating the cavernous nerve. The penises were then harvested for histologic examinations, ribonucleic acid (RNA), and protein levels of related factors by immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot. MAIN OUTCOME MEASURE: Erectile function was evaluated by maximum intracavernous pressure and mean arterial pressure. Penile tissues were used to perform histologic examinations and to determine the RNA and protein levels. RESULTS: Erectile function, which was impaired in rats with DMED, was significantly ameliorated in the DMED + rapamycin group. The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited in the DMED group, and rapamycin significantly reduced this inhibition. The DMED group showed increased autophagy and apoptosis level compared with the non-diabetic group, and rapamycin increased the autophagy level and decreased the apoptosis level in the penis. Penile fibrosis was more severe in the DMED group than in the control group and was partially but significantly improved in the DMED + rapamycin group compared with the DMED group. The adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin kinase (mTOR) and PI3K/AKT/mTOR pathways were activated, and the mTOR (regulatory associated protein of mTOR, complex 1 [raptor])/p70 ribosomal protein S6 kinase (p70S6K) pathway was inhibited in the DMED group. Compared with DMED group, rapamycin led to lower AMPK/mTOR and AKT/mTOR pathways expression, a higher degree of mTOR (raptor)/p70S6K pathway inhibition, and no change in the mTORC2-related pathway. CLINICAL IMPLICATIONS: Rapamycin was effective in restoring erectile function in type 1 DMED models. STRENGTH AND LIMITATIONS: This study suggested for the first time that rapamycin, an autophagy inducer, is effective in restoring erectile function in rats with diabetes. However, the rat model might not represent the human condition. CONCLUSION: Rapamycin improved erectile function in rats with DMED, likely by promoting autophagy, inhibiting apoptosis and fibrotic activity, and ameliorating endothelial function. These findings provide evidence of a potential treatment option for DMED. Lin H, Wang T, Ruan Y, et al. Rapamycin supplementation may ameliorate erectile function in rats with streptozotocin-induced type 1 diabetes by inducing autophagy and inhibiting apoptosis, endothelial dysfunction, and corporal fibrosis. J Sex Med 2018;15:1246-1259.
INTRODUCTION:Erectile dysfunction (ED), which is common in patients with diabetes mellitus (DM), seriously affects quality of life. Previous studies on the treatment of DM-induced ED (DMED) involve autophagy, but the specific effect and mechanism of treatment are not yet clear. AIM: To investigate the effect and mechanism of rapamycin, an autophagy inducer, in ameliorating DMED. METHODS: 45 male Sprague-Dawley rats (7 weeks old) were used in the experiment. 8 rats were randomly selected as the control group; the other rats were treated with streptozotocin to induce type 1 DM. After 10 weeks, an apomorphine test was used to confirm DMED. Rats with DMED were intraperitoneally injected with rapamycin or vehicle for 3 weeks. Rats in the control group were injected with saline. Erectile function in rats was measured by electrically stimulating the cavernous nerve. The penises were then harvested for histologic examinations, ribonucleic acid (RNA), and protein levels of related factors by immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot. MAIN OUTCOME MEASURE: Erectile function was evaluated by maximum intracavernous pressure and mean arterial pressure. Penile tissues were used to perform histologic examinations and to determine the RNA and protein levels. RESULTS: Erectile function, which was impaired in rats with DMED, was significantly ameliorated in the DMED + rapamycin group. The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited in the DMED group, and rapamycin significantly reduced this inhibition. The DMED group showed increased autophagy and apoptosis level compared with the non-diabetic group, and rapamycin increased the autophagy level and decreased the apoptosis level in the penis. Penile fibrosis was more severe in the DMED group than in the control group and was partially but significantly improved in the DMED + rapamycin group compared with the DMED group. The adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin kinase (mTOR) and PI3K/AKT/mTOR pathways were activated, and the mTOR (regulatory associated protein of mTOR, complex 1 [raptor])/p70 ribosomal protein S6 kinase (p70S6K) pathway was inhibited in the DMED group. Compared with DMED group, rapamycin led to lower AMPK/mTOR and AKT/mTOR pathways expression, a higher degree of mTOR (raptor)/p70S6K pathway inhibition, and no change in the mTORC2-related pathway. CLINICAL IMPLICATIONS: Rapamycin was effective in restoring erectile function in type 1 DMED models. STRENGTH AND LIMITATIONS: This study suggested for the first time that rapamycin, an autophagy inducer, is effective in restoring erectile function in rats with diabetes. However, the rat model might not represent the human condition. CONCLUSION:Rapamycin improved erectile function in rats with DMED, likely by promoting autophagy, inhibiting apoptosis and fibrotic activity, and ameliorating endothelial function. These findings provide evidence of a potential treatment option for DMED. Lin H, Wang T, Ruan Y, et al. Rapamycin supplementation may ameliorate erectile function in rats with streptozotocin-induced type 1 diabetes by inducing autophagy and inhibiting apoptosis, endothelial dysfunction, and corporal fibrosis. J Sex Med 2018;15:1246-1259.
Authors: Jian Xiong Ma; Bin Wang; Cai Fei Ding; Hai Song Li; Xue Juan Jiang; Chen Ye Wang; Jia Yu; Wang Qiang Chen Journal: Biosci Rep Date: 2020-02-28 Impact factor: 3.840