Identification of necroptosis-related features in diabetic nephropathy and analysis of their immune microenvironent and inflammatory response

Kaibo Hu; Ruifeng He; Minxuan Xu; Deju Zhang; Guangyu Han; Shengye Han; Leyang Xiao; Panpan Xia; Jitao Ling; Tingyu Wu; Fei Li; Yunfeng Sheng; Jing Zhang; Peng Yu

doi:10.3389/fcell.2023.1271145

Identification of necroptosis-related features in diabetic nephropathy and analysis of their immune microenvironent and inflammatory response

Front Cell Dev Biol. 2023 Nov 7:11:1271145. doi: 10.3389/fcell.2023.1271145. eCollection 2023.

Authors

Kaibo Hu^#^{1

2}, Ruifeng He^#^{1

2}, Minxuan Xu^{1

3

4}, Deju Zhang⁵, Guangyu Han^{1

2}, Shengye Han^{1

2}, Leyang Xiao^{1

2}, Panpan Xia^{1

3

4}, Jitao Ling^{1

3

4}, Tingyu Wu^{1

3

4}, Fei Li^{1

3

4}, Yunfeng Sheng^{1

3

4}, Jing Zhang⁶, Peng Yu^{1

3

4}

Affiliations

¹ Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
² The Second Clinical Medical College, Nanchang University, Nanchang, China.
³ Branch of National Clinical Research Center for Metabolic Diseases, Nanchang, China.
⁴ Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang, China.
⁵ Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
⁶ Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.

^# Contributed equally.

Abstract

Background: Diabetic nephropathy (DN) was considered a severe microvascular complication of diabetes, which was recognized as the second leading cause of end-stage renal diseases. Therefore, identifying several effective biomarkers and models to diagnosis and subtype DN is imminent. Necroptosis, a distinct form of programmed cell death, has been established to play a critical role in various inflammatory diseases. Herein, we described the novel landscape of necroptosis in DN and exploit a powerful necroptosis-mediated model for the diagnosis of DN. Methods: We obtained three datasets (GSE96804, GSE30122, and GSE30528) from the Gene Expression Omnibus (GEO) database and necroptosis-related genes (NRGs) from the GeneCards website. Via differential expression analysis and machine learning, significant NRGs were identified. And different necroptosis-related DN subtypes were divided using consensus cluster analysis. The principal component analysis (PCA) algorithm was utilized to calculate the necroptosis score. Finally, the logistic multivariate analysis were performed to construct the necroptosis-mediated diagnostic model for DN. Results: According to several public transcriptomic datasets in GEO, we obtained eight significant necroptosis-related regulators in the occurrence and progress of DN, including CFLAR, FMR1, GSDMD, IKBKB, MAP3K7, NFKBIA, PTGES3, and SFTPA1 via diversified machine learning methods. Subsequently, employing consensus cluster analysis and PCA algorithm, the DN samples in our training set were stratified into two diverse necroptosis-related subtypes based on our eight regulators' expression levels. These subtypes exhibited varying necroptosis scores. Then, we used various functional enrichment analysis and immune infiltration analysis to explore the biological background, immune landscape and inflammatory status of the above subtypes. Finally, a necroptosis-mediated diagnostic model was exploited based on the two subtypes and validated in several external verification datasets. Moreover, the expression level of our eight regulators were verified in the singe-cell level and glomerulus samples. And we further explored the relationship between the expression of eight regulators and the kidney function of DN. Conclusion: In summary, our necroptosis scoring model and necroptosis-mediated diagnostic model fill in the blank of the relationship between necroptosis and DN in the field of bioinformatics, which may provide novel diagnostic insights and therapy strategies for DN.

Keywords: diabetic nephropathy; diagnostic model; immune landscape; inflammatory response; necroptosis.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the National Natural Science Foundation of China (grant number 82160371 to JZ, 82100869 to PY); the Natural Science Foundation in Jiangxi Province (grant numbers 20212BAB216051 to JZ, 20212BAB216047 and 202004BCJL23049 to PY); the “Thousand Talents Plan” for Introducing and Cultivating High Level Talents in Innovation and Entrepreneurship of Jiangxi Province (grant number jxsq2023201105 to PY); the Innovation and Entrepreneurship Training Program for College Students in Jiangxi Province (grant number S202310403066 to RH).