Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis
Li Li,
Meizhi Lu,
Yiling Peng,
Junxin Huang,
Xiaoman Tang,
Jian Chen,
Jing Li,
Xue Hong,
Meizhi He,
Haiyan Fu,
Ruiyuan Liu,
Fan Fan Hou,
Lili Zhou,
Youhua Liu
Affiliations
Li Li
Corresponding author.; State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Meizhi Lu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Yiling Peng
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Junxin Huang
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Xiaoman Tang
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Jian Chen
Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, China
Jing Li
Department of Cardiology, The 924th Hospital of Chinese People’s Liberation Army Joint Service Support Force, Guilin, China
Xue Hong
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Meizhi He
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Haiyan Fu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Ruiyuan Liu
Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, China
Fan Fan Hou
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Lili Zhou
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Corresponding author.
Youhua Liu
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Corresponding author. Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis.
