Advanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress

Abstract

Diabetes severely impairs male reproduction. The present study assessed the effects and mechanisms of action of advanced glycation end products (AGEs), which play an important role in the development of diabetes complications, on testosterone secretion by rat Leydig cells. Primary rat Leydig cells were cultured and treated with AGEs (25, 50, 100 and 200 µg/ml). Testosterone production induced by human chorionic gonadotropin (hCG) was determined by ELISA. The mRNA and protein expression levels of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD), which are involved in testosterone biosynthesis, were measured by reverse transcription-quantitative PCR and western blot analyssi, respectively. Reactive oxygen species (ROS) production in Leydig cells was measured using the dichlorofluorescein diacetate (DCFH-DA) probe. The expression levels of endoplasmic reticulum stress-related proteins [C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78)] in the Leydig cells were measured by western blot analysis. We found that the AGEs markedly suppressed testosterone production by rat Leydig cells which was induced by hCG in a concentration-dependent manner compared with the control (P<0.01). The mRNA and protein expression levels of StAR, 3β-HSD and P450scc were downregulated by the AGEs in a dose-dependent manner compared with the control (P<0.01). The antioxidant agent, N-acetyl‑L‑cysteine (NAC), and the endoplasmic reticulum stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the inhibitory effects of AGEs. In addition, the content of ROS in Leydig cells treated with AGEs increased significantly. The expression levels of CHOP and GRP78 were markedly upregulated by the AGEs in the Leydig cells. From these findings, it can be concluded that AGEs inhibit testosterone production by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress.

Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

“…Chronic high glucose and AGEs in diabetes alter normal homeostasis, resulting in an increase in the generation of ROS3233. Treatment with Myr could effectively promote Nrf2 expression and its translocation to the nucleus, which in turn up-regulated HO-1, NQO-1, and γ-GCS to eliminate ROS both in vitro (Fig.…”

The Role of Endoplasmic Reticulum Stress Response in Male Reproductive Physiology and Pathology: A Review

“…Another study in streptozotocin-induced diabetic animal model showed activation of testicular oxidative stress; mitochondrial cell death and associated p38 MAPK and p53 signaling; and ER stress and associated cell death [36,52]. Similarly, in vitro study, advanced glycation end products, a heterogeneous compound in the progression of diabetes, inhibit the generation of testosterone by upregulation the ER stress related protein Grp78 and CHOP in Leydig cells [53]. Human chorionic gonadotropin (hCG) secreted by placenta, is heterodimeric protein hormone to luteinizing hormone and exogenous hCG has been used clinically to increase plasma testosterone in disease, such as hypogonadotropic hypogonadism, cryptorchidism.…”

Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats

“…As testicular damage due to ageing is considered as a serious complication for males, its delay and prevention become clinically important. As it is known, oxidative stress, increased glycation products and poor antioxidant system appear to be among the main causes of testicular disruption (Güneş, Hekim, Arslan, & Aşcı, ; Zhao, Qi, Hu, Chen, & Liu, ). Therefore, the first aim of this study was to investigate the effect of GAL treatment on prooxidant–antioxidant balance and glycation products in testis tissue.…”

“…This decrease is considered to be related to oxidative stress‐induced damage of Leydig cells (Zirkin & Tenover, ). In addition, AGE were also reported to inhibit testosterone production by Leydig cells through inducing oxidative and endoplasmic reticulum stresses (Zhao et al., ). In the present study, serum testosterone levels were also found to decrease in GAL‐treated rats.…”