Pharmacological targets of SGLT2 inhibitors on IgA nephropathy and membranous nephropathy: a mendelian randomization study

Xin Lv; Yan Shang; Yong Ning; Weimin Yu; Jian Wang

doi:10.3389/fphar.2024.1399881

Pharmacological targets of SGLT2 inhibitors on IgA nephropathy and membranous nephropathy: a mendelian randomization study

Front Pharmacol. 2024 May 22:15:1399881. doi: 10.3389/fphar.2024.1399881. eCollection 2024.

Authors

Xin Lv^{1

2}, Yan Shang^{1

2}, Yong Ning^{1

2}, Weimin Yu^{1

2}, Jian Wang³

Affiliations

¹ Department of Nephrology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China.
² Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.

Abstract

Introduction: Emerging research suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may play a pivotal role in the treatment of primary glomerular diseases. This study was aimed to investigate potential pharmacological targets connecting SGLT2 inhibitors with IgA nephropathy (IgAN) and membranous nephropathy (MN).

Methods: A univariate Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies (GWAS) datasets. Co-localization analysis was used to identify potential connections between target genes and IgAN and MN. Then, Comparative Toxicogenomics Database (CTD) was employed to predict diseases associated with these target genes and SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin). Subsequently, phenotypic scan analyses were applied to explore the causal relationships between the predicted diseases and target genes. Finally, we analyzed the immune signaling pathways involving pharmacological target genes using the Kyoto encyclopedia of genes and genomes (KEGG).

Results: The results of MR analysis revealed that eight drug targets were causally linked to the occurrence of IgAN, while 14 drug targets were linked to MN. In the case of IgAN, LCN2 and AGER emerged as co-localized genes related to the pharmacological agent of dapagliflozin and the occurrence of IgAN. LCN2 was identified as a risk factor, while AGER was exhibited a protective role. KEGG analysis revealed that LCN2 is involved in the interleukin (IL)-17 immune signaling pathway, while AGER is associated with the neutrophil extracellular traps (NETs) signaling immune pathway. No positive co-localization results of the target genes were observed between two other SGLT2 inhibitors (canagliflozin and empagliflozin) and the occurrence of IgAN, nor between the three SGLT2 inhibitors and the occurrence of MN.

Conclusion: Our study provided evidence supporting a causal relationship between specific SGLT2 inhibitors and IgAN. Furthermore, we found that dapagliflozin may act on IgAN through the genes LCN2 and AGER.

Keywords: IgA nephropathy; SGLT2 inhibitors; co-location analysis; membranous nephropathy; mendelian randomization.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by Fundamental Research Program of Shanxi Procince (No. 20210302124569), and Scientific Research Funding of Shanxi Bethune Hospital (no.2023GZRZ30).