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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Renal Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1399881

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

Provisionally accepted
Xin Lv Xin Lv 1Yan Shang Yan Shang 1Yong Ning Yong Ning 1Weimin Yu Weimin Yu 1Jian Wang Jian Wang 2*
  • 1 Department of Nephrology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
  • 2 Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, China

The final, formatted version of the article will be published soon.

    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).A univariate Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association study (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).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.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: SGLT2 inhibitors, Membranous nephropathy, IgA nephropathy, Co-location analysis, Mendelian randomization

    Received: 12 Mar 2024; Accepted: 30 Apr 2024.

    Copyright: © 2024 Lv, Shang, Ning, Yu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jian Wang, Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, China

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