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.
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.
To investigate the effect and mechanism of rapamycin, an autophagy inducer, in ameliorating DMED.
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.
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.
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.
Rapamycin was effective in restoring erectile function in type 1 DMED models.
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.
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.
Lin H
，Wang T
，Ruan Y
，Liu K
，Li H
，Wang S
，Li M
，Liu J
... -
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Probucol improves erectile function via Activation of Nrf2 and coordinates the HO-1 / DDAH / PPAR-γ/ eNOS pathways in streptozotocin-induced diabetic rats.
Diabetic erectile dysfunction (DMED) is mainly attributed to oxidative stress, and Nrf2 plays an important role in cellular antioxidation and regulates NO production in the vascular endothelium. Probucol maintains endothelial function through its antioxidant activity. This study investigated the efficacy and mechanism of probucol in improving erectile function in streptozotocin-induced diabetic rats.
In our study, thirty 12-week-old Sprague-Dawley male rats were fasted for 12 h. All rats received a 1-time injection of intraperitoneal streptozotocin(60 mg/kg) or vehicle. After 72 h, STZ-treated rats (with random blood glucose concentrations consistently greater than 16.7 mmol/L) were considered diabetic. The diabetic rats were randomly assigned into 2 groups and treated with daily gavage feedings of probucol at doses of 0 and 500 mg/kg for 12 weeks. A positive control group underwent intraperitoneal injection of normal saline followed by daily gavage of saline solution. Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated using immunohistochemistry, Western blot, and ELISA to assess the proteins of Nrf2/HO-1/DDAH/PPAR-γ/eNOS pathways.
After treatment, the rats in the probucol group presented significantly improved erectile function (P < 0.05) than that of the diabetic group without probucol treatment (DM). Also, protein expression of Nrf2, DDAH, PPAR-γ, HO-1 and eNOS was significantly higher than that of the DM group (P < 0.05). CGMP concentrations and SOD concentrations of probucol-treated rats were higher than those of DM group (P < 0.05). The MDA levels and ADMA levels were significantly lower than those of DM group rats (P < 0.05).
Probucol can improve erectile function via activation of Nrf2, which coordinates the HO-1/DDAH/PPAR-γ/eNOS pathways in streptozotocin-induced diabetic rats.
Hu LL
，Zhang KQ
，Tian T
，Zhang H
，Fu Q
... -
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Probucol Improves Erectile Function by Restoring Endothelial Function and Preventing Cavernous Fibrosis in Streptozotocin-induced Diabetic Rats.
To investigate the effects of probucol on erectile function in streptozotocin-induced diabetic rats and explore the underlying mechanisms.
A total of thirty 12-week-old Sprague-Dawley male rats received a 1-time intraperitoneal streptozotocin (60 mg/kg) or vehicle injection after a 12-hour fast. Three days later, the streptozotocin-induced diabetic rats were randomly divided into 2 groups and were treated with daily gavage feedings of probucol at doses of 0 and 500 mg/kg for 12 weeks. A positive control group underwent intraperitoneal injection of saline followed by daily gavage of saline solution. Erectile function was assessed by electrical stimulation of the cavernous nerves with real-time intracavernous pressure measurement. After euthanasia, penile tissue was investigated using immunohistochemistry, Western blot, and ELISA to assess the protein arginine-N-methyltransferase 1/dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine/nitric oxide synthase metabolism pathway. Superoxide dismutase activity and malondialdehyde levels were detected by colorimetry. We also evaluated penile histological changes such as smooth muscle contents and Masson's trichrome stain.
Significant recovery of erectile function was observed in the probucol-treated rats than the untreated diabetic rats. The protein expression of dimethylarginine dimethylaminohydrolase and nitric oxide synthase, cyclic guanosine monophosphate concentrations, and superoxide dismutase activity in cavernous tissue of probucol-treated rats were significantly higher than the untreated diabetic rats. The protein expression of protein arginine-N-methyltransferase 1, asymmetric dimethylarginine concentrations, and malondialdehyde levels in cavernous tissue of probucol-treated rats were significantly lower than the untreated diabetic rats. In addition, probucol treatment markedly augments the cavernous smooth muscle content.
Probucol treatment improves erectile function by restoring endothelial function and preventing cavernous fibrosis in streptozotocin-induced diabetic rats.
Zhang KQ
，Chen D
，Sun DQ
，Zhang H
，Li B
，Fu Q
... -
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