Partial reduction of interleukin‐33 signaling improves senescence and renal injury in diabetic nephropathy
Li Chen,
Chao Gao,
Xingzhu Yin,
Li Mo,
Xueer Cheng,
Huimin Chen,
Chunjie Jiang,
Bangfu Wu,
Ying Zhao,
Hongxia Li,
Yanyan Li,
Jiansha Li,
Liangkai Chen,
Qianchun Deng,
Ping Yao,
Yuhan Tang
Affiliations
Li Chen
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Chao Gao
National Institute for Nutrition and Health Chinese Center for Disease Control and Prevention Beijing Beijing China
Xingzhu Yin
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Li Mo
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Xueer Cheng
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Huimin Chen
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Chunjie Jiang
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Bangfu Wu
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Ying Zhao
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Hongxia Li
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Yanyan Li
Shenzhen Center for Chronic Disease Control Shenzhen China
Jiansha Li
Institute of Pathology Tongji Hospital Wuhan China
Liangkai Chen
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Qianchun Deng
Oil Crops Research Institute of the Chinese Academy of Agricultural Sciences Hubei Key Laboratory of Lipid Chemistry and Nutrition and Key Laboratory of Oilseeds Processing Ministry of Agriculture Oil Crops and Lipids Process Technology National & Local Joint Engineering Laboratory Wuhan Hubei China
Ping Yao
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Yuhan Tang
Department of Nutrition and Food Hygiene Hubei Key Laboratory of Food Nutrition and Safety Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health Key Laboratory of Environment and Health (Wuhan) Ministry of Environmental Protection State Key Laboratory of Environment Health (Incubation) School of Public Health Tongji Medical College Huazhong University of Science and Technology Wuhan China
Abstract Diabetic nephropathy (DN) is a frequent and costly complication of diabetes with limited understandings of mechanisms and therapies. Emerging evidence points to the important roles of interleukin‐33 (IL‐33) in acute kidney injury, yet its contribution to DN is still unclear. We here found a ubiquitous increase of IL‐33 and its receptor (ST2) in murine models and patients with DN. Surprisingly, both IL‐33 and ST2 knockdown aggravated renal lesions in DN, while overexpression of IL‐33 also exacerbated the condition. Further population‐based analyses revealed a positive correlation of IL‐33 expression with renal dysfunction in DN patients. Individuals with high IL‐33 expression‐related polygenic risk score had a higher DN risk. These findings confirmed the harmful effects of IL‐33 on DN. Conversely, endogenous and exogenous partial reduction of IL‐33 signaling conferred renoprotective effects in vivo and in vitro. Mechanistically, IL‐33 induced senescence by regulating cell cycle factors in HK‐2 cells, and accordingly senescence led to renal cell damage through the secretion of senescence‐related secretory phenotype (SASP) including IL‐33 and prostaglandins. Together, elevated IL‐33 accelerates cellular senescence to drive DN possibly by SASP production, while a partial blockage improves renal injury and senescence. Our findings pinpoint a possible and new avenue for DN interventions.
