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

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. · pubmed

Paper

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.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper investigates the role of interleukin-33 in diabetic nephropathy, linking it to cellular senescence and renal injury. While it addresses mechanisms that could contribute to aging-related diseases, it primarily focuses on a specific condition rather than the broader implications for aging or lifespan extension. The findings provide solid insights into the pathology of diabetic nephropathy and suggest potential therapeutic avenues, but they do not fundamentally alter our understanding of aging itself. Thus, it represents a solid contribution but with limited impact on the broader field of longevity research.

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