Functional genomics reveals adipose-kidney crosstalk as a contributor to kidney fibrosis via the OSM-OSMR pathway.

IF 3.1 4区生物学 Q1 GENETICS & HEREDITY

Functional & Integrative Genomics Pub Date : 2025-06-02 DOI:10.1007/s10142-025-01624-y

Jing Zhang, Zhaojun Liu, Shihui Dong, Kun Xu, Kangchun Wang, Luyu Gong, Qiaoqiao Liu, Yue Guo, Yeping Zhu, Jingrong She, Song Jiang, Shaolin Shi, Zhihong Liu, Jingping Yang

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引用次数: 0

Abstract

Kidney injury is a severe complication of type 2 diabetes, yet its pathophysiology varies among patients. Although abnormal adipose has been identified as an indicator for the risk of kidney injury in type 2 diabetes, the underlying mechanisms remain unclear. Here, we integrated adipose functional genomics and genome-wide association studies of diabetic nephropathy (DN) to investigate the relationship between adipose and kidney injury. By generating the epigenome, transcriptome and regulatome, we constructed functional genomics map of adipose, revealing the regulatory role of perirenal adipose tissue in kidney disease. Integration of the functional genomics with genetic risk demonstrated that the genetic risk of DN is mediated not only through the kidney itself but also via adipose-kidney crosstalk. Our results revealed that risk variant rs2412980 functions through an adipose-specific regulatory element to control the expression of OSM, encoding the cytokine oncostatin-M. Adipose-derived OSM can reprogram OSMR-expressing renal fibroblasts, and subsequent activation of OSM-OSMR pathway is associated with advanced kidney injury, including reduced eGFR, elevated proteinuria and creatinine levels. Our work confirmed the linkage between adipose and kidney diseases with the genetic evidence, and revealed that the adipo-renal axis promotes the fibrosis of kidney under diabetes through the OSM-OSMR pathway.

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功能基因组学揭示，脂肪-肾脏串扰通过osmm - osmr途径促进肾脏纤维化。

肾损伤是2型糖尿病的严重并发症，但其病理生理在不同患者之间存在差异。尽管异常脂肪已被确定为2型糖尿病肾损伤风险的一个指标，但其潜在机制尚不清楚。在这里，我们整合了脂肪功能基因组学和糖尿病肾病（DN）的全基因组关联研究来研究脂肪和肾损伤之间的关系。通过生成表观基因组、转录组和调节组，构建脂肪功能基因组图谱，揭示肾周脂肪组织在肾脏疾病中的调节作用。功能基因组学与遗传风险的整合表明，DN的遗传风险不仅通过肾脏本身介导，还通过脂肪-肾脏串扰介导。我们的研究结果表明，风险变异rs2412980通过脂肪特异性调控元件控制OSM的表达，编码细胞因子oncostatin-M。脂肪来源的OSM可以重编程表达osmr的肾成纤维细胞，随后OSM- osmr通路的激活与晚期肾损伤相关，包括eGFR降低、蛋白尿和肌酐水平升高。我们的工作以遗传证据证实了脂肪和肾脏疾病之间的联系，并揭示了脂肪-肾脏轴通过OSM-OSMR途径促进糖尿病肾脏纤维化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Functional & Integrative Genomics 生物-遗传学

CiteScore

3.50

自引率

3.40%

发文量

审稿时长

2 months

期刊介绍： Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?