Dapagliflozin’s Association with LCN2, AGER Suggest Therapeutic Effect in IgA Nephropathy

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A recent analysis of the relationship between genes associated with IgA nephropathy (IgAN) and membranous nephropathy (MN) with the target genes of sodium-glucose cotransporter 2 (SGLT2) inhibitors found instances of co-localization between the target genes of SGLT2 inhibitors and the pathogenesis genes of MN and IgAN.¹

Findings from the Mendelian randomization (MR) analysis identified LCN2 and AGER as genes co-located with the dapagliflozin target gene and the IgAN pathogenesis gene, although the study did not find a positive co-localization relationship between the target gene of SGLT2 inhibitors and the pathogenesis gene of MN.¹

“Although some studies have explored the effect of SGLT2 inhibitors on renal diseases, a comprehensive understanding of their exact mechanisms and roles in primary renal diseases remains a topic for further research,” Jian Wang, PhD, of the department of nephrology at the First Affiliated Hospital of Gannan Medical University in China, and colleagues wrote.¹

Originally developed as oral antidiabetic drugs, SGLT2 inhibitors later showed benefit in clinical trials for improving kidney health in people with heart failure and/or CKD. They help reduce blood sugar levels by preventing the kidneys from reabsorbing sugar and excreting it through urine.² Although the effect of SGLT2 inhibitors on renal diseases has been explored in some studies, this research has not provided a comprehensive understanding of their exact mechanisms and roles in primary renal diseases.

To investigate potential pharmacological targets connecting SGLT2 inhibitors with IgAN and MN and explore the bidirectional causal relationship, investigators conducted univariate MR analyses using publicly available genome-wide association studies datasets. Those related to IgAN (ieu-a-1081) consisted of 278,077 single nucleotide polymorphisms (SNPs) and included a cohort of 595,700 samples. Additionally, the dataset for MN (ebi-a-GCST010005) encompassed 797,900 samples and featured 532,768 SNPs. Independent SNPs that demonstrated significant relevance to the exposure factors were required to meet the following criteria: P < 5 × 10-8, R2 ≥ 0.001, and linkage disequilibrium distances ≥10 kb.¹

Investigators focused on 3 SGLT2 inhibitors, namely canagliflozin, dapagliflozin, and empagliflozin, and obtained their associated target genes from the Comparative Toxicogenomics Database. Co-localization analysis was used to identify potential connections between these target genes and IgAN and MN.¹

Investigators identified 8 drug targets causally linked to the occurrence of IgAN (AGER; ATF6; CASP7; JAK2; LCN2; MPO; CAT; and ELF2), and 14 drug targets linked to MN (ACTA2; ATF6; CD36; CDH1; IL1B; INSR; JAK2; MAP1LC3B; MTOR; OGA; PPARA; PTGS2; VIM; and DDIT3).¹

To determine the presence of shared genetic signals between IgAN and the identified 8 target genes, investigators conducted comprehensive colocalization analyses and found LCN2 expression and IgAN shared a causal variant, rs3099844 (pP.H4 = 0.935,308). Similarly, they noted AGER expression and IgAN also shared causal variants, specifically rs3130349 (pP.H4 = 0.988,317) and rs3130696 (pP.H4 = 0.961,451). However, no positive co-localization results were observed between MN and 14 genes with a significant causal relationship.¹

Based on these results, investigators suggested a positive association between LCN2 expression and IgAN while noting AGER might act as a protective factor against IgAN. Of note, both LCN2 and AGER were found to correspond to dapagliflozin, but no evidence of positive co-localization of target genes was observed between canagliflozin or empagliflozin and the occurrence of IgAN. Regarding the absence of co-localization in MN, investigators leveraged this as evidence challenging the idea of an association driven by specific target genes within MN.¹

Further analysis of the immune signaling pathways involving pharmacological target genes using the Kyoto Encyclopedia of Genes and Genomes revealed a significant association between LCN2 and the interleukin-17 signaling pathway, while AGER showed potential involvement in the AGE-RAGE signaling pathway in diabetic complications and Neutrophil extracellular trap formation.¹

Investigators outlined several potential limitations to these findings, including the use of data sourced mainly from European populations; the lack of estimation of the potential off-target effects; and the possibility of horizontal pleiotropy despite various sensitivity analyses.¹

“The study identified instances of co-localization between the target genes of SGLT2 inhibitors and the pathogenesis genes of MN and IgAN. Specifically, LCN2 and AGER emerged as genes co-located with the dapagliflozin target gene and the IgAN pathogenesis gene. Importantly, the study did not find a positive co-localization relationship between the target gene of SGLT2 inhibitors and the pathogenesis gene of MN,” investigators concluded.¹

References:

1. ^{Lv X, Shang Y, Ning Y, Yu W and Wang J (2024) Pharmacological targets of SGLT2 inhibitors on IgA nephropathy and membranous nephropathy: a mendelian randomization study. Front. Pharmacol. 15:1399881. doi:10.3389/fphar.2024.1399881}
2. ^{National Kidney Foundation. Sodium-glucose cotransporter-2 (SGLT2) inhibitors. Accessed June 18, 2024. https://www.kidney.org/atoz/content/sglt2-inhibitors}