PMID- 30224017 OWN - NLM STAT- MEDLINE DCOM- 20191021 LR - 20191022 IS - 1743-6109 (Electronic) IS - 1743-6095 (Linking) VI - 15 IP - 9 DP - 2018 Sep TI - 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. PG - 1246-1259 LID - S1743-6095(18)31098-1 [pii] LID - 10.1016/j.jsxm.2018.07.013 [doi] AB - 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. CI - Copyright (c) 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. FAU - Lin, Huang AU - Lin H AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. FAU - Wang, Tao AU - Wang T AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. FAU - Ruan, Yajun AU - Ruan Y AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. FAU - Liu, Kang AU - Liu K AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. FAU - Li, Hao AU - Li H AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. FAU - Wang, Shaogang AU - Wang S AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. FAU - Li, Mingchao AU - Li M AD - 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. FAU - Liu, Jihong AU - Liu J AD - Department of Urology and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Netherlands TA - J Sex Med JT - The journal of sexual medicine JID - 101230693 RN - 5W494URQ81 (Streptozocin) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects MH - Diabetes Mellitus, Experimental/*complications/physiopathology MH - Diabetes Mellitus, Type 1/*complications MH - Disease Models, Animal MH - Erectile Dysfunction/complications/*drug therapy/physiopathology MH - Injections, Intraperitoneal MH - Male MH - Penile Erection/drug effects MH - Rats MH - Rats, Sprague-Dawley MH - Sirolimus/administration & dosage/pharmacology/*therapeutic use MH - Streptozocin OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Diabetes Mellitus OT - Erectile Function OT - Fibrosis EDAT- 2018/09/19 06:00 MHDA- 2019/10/23 06:00 CRDT- 2018/09/19 06:00 PHST- 2018/04/25 00:00 [received] PHST- 2018/07/16 00:00 [revised] PHST- 2018/07/23 00:00 [accepted] PHST- 2018/09/19 06:00 [entrez] PHST- 2018/09/19 06:00 [pubmed] PHST- 2019/10/23 06:00 [medline] AID - S1743-6095(18)31098-1 [pii] AID - 10.1016/j.jsxm.2018.07.013 [doi] PST - ppublish SO - J Sex Med. 2018 Sep;15(9):1246-1259. doi: 10.1016/j.jsxm.2018.07.013.