达格列净对糖尿病大鼠睾丸损伤的保护效应

Protective effect of dapagliflozin against testicular injury in diabetic rats

目的观察SGLT-2抑制剂达格列净对糖尿病大鼠睾丸损伤的影响。方法雄性SD大鼠随机分为正常组、2型糖尿病(T2DM)组和达格列净组,每组6只。T2DM组和达格列净组采用高糖高脂饮食配合链脲佐菌素(STZ)诱导大鼠T2DM模型,达格列净组予以达格列净治疗。干预8周后,测定血糖、血睾酮及睾丸质量系数。HE染色观察睾丸组织形态改变。检测睾丸组织中丙二醛(MDA)和超氧化物歧化酶(SOD)的表达水平。实时定量PCR(RT-PCR)检测睾丸组织中NLRP3、ASC、Caspase-1、IL-1β、TNF-α和TGF-β1的mRNA表达水平。结果相比于正常组,T2DM组大鼠血糖和睾丸质量系数明显增加(P<0.001),血睾酮水平降低(P<0.001);睾丸组织中生精细胞层数及数量减少,排列紊乱;MDA水平明显增加(P<0.001),SOD水平明显下降(P<0.01);NLRP3、ASC、Caspase-1、IL-1β、TNF-α和TGF-β1的mRNA水平明显增加(P<0.001)。与T2DM组大鼠比较,达格列净干预后血糖、睾丸质量系数明显下降(P<0.001),血睾酮水平增高(P<0.001);睾丸病理损害好转,MDA表达下降(P<0.001),SOD表达增高(P<0.05);NLRP3、ASC、Caspase-1、IL-1β、TNF-α和TGF-β1的mRNA水平显著降低(P<0.01)。结论糖尿病大鼠睾丸激素水平表达异常,睾丸组织出现病理变化,发生炎症反应和氧化应激。达格列净可能通过调节NLRP3/ASC/Caspase-1炎性小体通路减轻炎症反应及氧化应激,从而减轻糖尿病所致的睾丸损害。

Objective To observe the effect of SGLT-2 inhibitor dapagliflozin on testicular damage in diabetic rats.Methods Male SD rats were divided randomly into three groups(n=6 in each group):normal group,T2DM group and dapagliflozin group.The rats in T2DM group and dapagliflozin group were fed with high-sugar and high-fat diet and injected with streptozotocin(STZ)to induce type 2 diabetes(T2DM)model,and the rats in dapagliflozin group were treated with 10 mg/kg of dapagliflozin every day.At week 8 after intervention,blood glucose,testosterone and testicular mass coefficient were measured.HE staining was used to observe the changes in testicular tissue.The expression levels of malondialdehyde(MDA)and superoxide dismutase(SOD)were detected in testicular tissues.RT-PCR was used to detect the mRNA levels of NLRP3,ASC,Caspase-1,IL-1β,TNF-αand TGF-β1 in testicular tissues.Results Compared with normal group,the blood glucose and the testicular mass coefficient were increased significantly in T2DM group(P<0.001),while the blood testosterone level was decreased(P<0.001);the number of spermatogenic cells in the testicular tissue was decreased,and the arrangement was disordered;the level of MDA was increased significantly(P<0.001),and the level of SOD was decreased significantly(P<0.01);and NLRP3,ASC,Caspase-1,IL-1β,TNF-αand TGF-β1 mRNA levels were increased significantly(P<0.001).Compared with T2DM group,the blood glucose and the testicular mass coefficient were significantly decreased after intervention in dapagliflozin group(P<0.001),while the blood testosterone level was increased(P<0.001);testicular pathological damage was improved;MDA expression was decreased(P<0.001),while SOD expression was increased(P<0.05);and the mRNA levels of NLRP3,ASC,Caspase-1,IL-1β,TNF-αand TGF-β1 were significantly reduced.Conclusion The expression of testosterone in diabetic rats is abnormal,with pathological changes of the testicular tissue,and inflammation and oxidative stress.Dapagliflozin may reduce the inflammation and the oxidative stress by regulating the NLRP3/ASC/Caspase-1 inflammasome signaling pathway,thereby reducing the testicular damage caused by diabetes.