Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress

Diabetic nephropathy (DN) has become the most common secondary kidney disease causing end-stage renal disease (ESRD). Nevertheless, the underlying mechanisms responsible for DN remain largely unknown. Regulated in development and DNA damage response 1 (REDD1) is a prooxidative molecule known to cont...

Full description

Saved in:
Bibliographic Details
Main Authors: Lin Mu, Nan Chen, Yakun Chen, Zhifen Yang, Huandi Zhou, Shan Song, Yonghong Shi
Format: Article
Language:English
Published: Wiley 2022-01-01
Series:International Journal of Endocrinology
Online Access:http://dx.doi.org/10.1155/2022/6073911
Tags: Add Tag
No Tags, Be the first to tag this record!
_version_ 1832562092084822016
author Lin Mu
Nan Chen
Yakun Chen
Zhifen Yang
Huandi Zhou
Shan Song
Yonghong Shi
author_facet Lin Mu
Nan Chen
Yakun Chen
Zhifen Yang
Huandi Zhou
Shan Song
Yonghong Shi
author_sort Lin Mu
collection DOAJ
description Diabetic nephropathy (DN) has become the most common secondary kidney disease causing end-stage renal disease (ESRD). Nevertheless, the underlying mechanisms responsible for DN remain largely unknown. Regulated in development and DNA damage response 1 (REDD1) is a prooxidative molecule known to contribute to diabetes mellitus and its complications. However, it has not been previously examined whether and how REDD1 can further drive renal tubular epithelial cell (RTEC) apoptosis and epithelial-to-mesenchymal transition in DN. The expression of REDD1 was elevated in the kidneys of DN patients and diabetic mice in this study. By generating the DN model in REDD1 knockout mice, we demonstrated that REDD1 deficiency significantly improved apoptosis and EMT in diabetic mice. In vitro experiments showed that REDD1 generation was induced by high glucose (HG) in HK-2 cells. Similarly, the transfection of REDD1 siRNA plasmid also suppressed HG-induced apoptosis and EMT. Furthermore, we discovered that the inhibition of REDD1 suppressed the expression of Nox4-induced HG and reactive oxygen species (ROS) synthesis in HK-2 cells. In addition, HG could induce endogenous REDD1 and TXNIP to form a powerful complex. In summary, our findings demonstrate that blocking the REDD1/TXNIP complex can prevent HG-induced apoptosis and EMT by inhibiting ROS production, highlighting REDD1 as a valuable therapeutic priority site for DN.
format Article
id doaj-art-fa5785edd79349fba71e38cee71f5761
institution Kabale University
issn 1687-8345
language English
publishDate 2022-01-01
publisher Wiley
record_format Article
series International Journal of Endocrinology
spelling doaj-art-fa5785edd79349fba71e38cee71f57612025-02-03T01:23:35ZengWileyInternational Journal of Endocrinology1687-83452022-01-01202210.1155/2022/6073911Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative StressLin Mu0Nan Chen1Yakun Chen2Zhifen Yang3Huandi Zhou4Shan Song5Yonghong Shi6Department of PathologyDepartment of PathologyDepartment of NephrologyDepartment of PathologyDepartment of PathologyDepartment of PathologyDepartment of PathologyDiabetic nephropathy (DN) has become the most common secondary kidney disease causing end-stage renal disease (ESRD). Nevertheless, the underlying mechanisms responsible for DN remain largely unknown. Regulated in development and DNA damage response 1 (REDD1) is a prooxidative molecule known to contribute to diabetes mellitus and its complications. However, it has not been previously examined whether and how REDD1 can further drive renal tubular epithelial cell (RTEC) apoptosis and epithelial-to-mesenchymal transition in DN. The expression of REDD1 was elevated in the kidneys of DN patients and diabetic mice in this study. By generating the DN model in REDD1 knockout mice, we demonstrated that REDD1 deficiency significantly improved apoptosis and EMT in diabetic mice. In vitro experiments showed that REDD1 generation was induced by high glucose (HG) in HK-2 cells. Similarly, the transfection of REDD1 siRNA plasmid also suppressed HG-induced apoptosis and EMT. Furthermore, we discovered that the inhibition of REDD1 suppressed the expression of Nox4-induced HG and reactive oxygen species (ROS) synthesis in HK-2 cells. In addition, HG could induce endogenous REDD1 and TXNIP to form a powerful complex. In summary, our findings demonstrate that blocking the REDD1/TXNIP complex can prevent HG-induced apoptosis and EMT by inhibiting ROS production, highlighting REDD1 as a valuable therapeutic priority site for DN.http://dx.doi.org/10.1155/2022/6073911
spellingShingle Lin Mu
Nan Chen
Yakun Chen
Zhifen Yang
Huandi Zhou
Shan Song
Yonghong Shi
Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress
International Journal of Endocrinology
title Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress
title_full Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress
title_fullStr Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress
title_full_unstemmed Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress
title_short Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress
title_sort blocking redd1 txnip complex ameliorates hg induced renal tubular epithelial cell apoptosis and emt through repressing oxidative stress
url http://dx.doi.org/10.1155/2022/6073911
work_keys_str_mv AT linmu blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress
AT nanchen blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress
AT yakunchen blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress
AT zhifenyang blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress
AT huandizhou blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress
AT shansong blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress
AT yonghongshi blockingredd1txnipcomplexameliorateshginducedrenaltubularepithelialcellapoptosisandemtthroughrepressingoxidativestress