NRF2 Plays a Critical Role in Both Self and EGCG Protection against Diabetic Testicular Damage.

Chenyu Pan,Yanyan Song,Jingyan Tian,Lijuan Ha,Hao Wu,Junduo Wu,Lingyun Liu,Fuchun Wang,Xiaona Liu,Shengzhu Zhou,Tie Li

doi:10.1155/2017/3172692

Abstract

Activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been found to ameliorate diabetic testicular damage (DTD) in rodents. However, it was unclear whether NRF2 is required for these approaches in DTD. Epigallocatechin gallate (EGCG) is a potent activator of NRF2 and has shown beneficial effects on multiple diabetic complications. However, the effect of EGCG has not been studied in DTD. The present study aims to explore the role of NRF2 in both self and EGCG protection against DTD. Therefore, streptozotocin-induced diabetic C57BL/6 wild type (WT) and Nrf2 knockout (KO) mice were treated in the presence or absence of EGCG, for 24 weeks. The Nrf2 KO mice exhibited more significant diabetes-induced loss in testicular weight and spermatozoa count, and increase in testicular apoptotic cell death, as compared with the WT mice. EGCG activated NRF2 expression and function, preserved testicular weight and spermatozoa count, and attenuated testicular apoptotic cell death, endoplasmic reticulum stress, inflammation, and oxidative damage in the WT diabetic mice, but not the Nrf2 KO diabetic mice. The present study demonstrated for the first time that NRF2 plays a critical role in both self and EGCG protection against DTD.

Highlights

Diabetes causes damage to multiple organs, including testis [1]
Nuclear factor erythroid 2-related factor 2 (NRF2) activates the transcription of a cohort of antioxidant genes, such as heme oxygenase-1 (Ho1) and NAD(P)H dehydrogenase quinone 1 (Nqo1) [11], the proteins of which work as scavengers of diabetes-induced free radicals
The Nrf2 KO diabetic mice suffered from more marked decrease in the two indices, as compared with the wild type (WT) diabetic mice (Figures 1(c) and 1(d))

Summary

Introduction

Diabetes causes damage to multiple organs, including testis [1]. Decreased sperm cell count and velocity were found in patients with diabetes [2]. Diabetics had increased sperm nuclear and mitochondrial DNA damage [3], along with increased level of advanced glycation end products (AGEs) in the testis, epididymis, and sperm [4]. Diabetesinduced excessive AGEs can cause oxidative stress, leading to activation of mitochondria or endoplasmic reticulum (ER) stress-related cell death pathways, the effect of which may result in sperm loss [5,6,7,8]. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master factor in the cellular antioxidant system [9, 10]. NRF2 activates the transcription of a cohort of antioxidant genes, such as heme oxygenase-1 (Ho1) and NAD(P)H dehydrogenase quinone 1 (Nqo1) [11], the proteins of which work as scavengers of diabetes-induced free radicals.

Methods

Results

Conclusion