SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression

Kim, Ye Jin; Jin, Jonghwa; Kim, Dong-Ho; Kim, Daehoon; Lee, You Mie; Byun, Jun-Kyu; Choi, Yeon-Kyung; Park, Keun-Gyu

doi:10.1007/s00011-023-01796-y

Cited by 5 publications

(2 citation statements)

References 63 publications

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“…Other significant pathways identified by Kyoto Encyclopedia of Genes and Genomes analysis, such as glycolysis, are vital in IBD [ 64 ]. The energy and metabolites produced by glycolysis support the development and metabolism of bowel microbiota [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy

Yan,

Zhao,

Liu

et al. 2024

Renal Failure

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The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify the optimal cross-talk genes, potential pathways, and mutual immune-infiltrating microenvironments between IBD and IgAN to elucidate the linkage between patients with IBD and IgAN. The IgAN and IBD datasets were obtained from the Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, and xCell, were used to evaluate the similarities in the infiltrating microenvironment between the two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented in the IBD dataset to identify the major immune infiltration modules, and the Boruta algorithm, RFE algorithm, and LASSO regression were applied to filter the cross-talk genes. Next, multiple machine learning models were applied to confirm the optimal cross-talk genes. Finally, the relevant findings were validated using histology and immunohistochemistry analysis of IBD mice. Immune infiltration analysis showed no significant differences between IBD and IgAN samples in most immune cells. The three algorithms identified 10 diagnostic genes, MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, and RIPK2; FDX1 and NFKB1 were enhanced in the kidney of IBD mice. Kyoto Encyclopedia of Genes and Genomes analysis showed 15 mutual pathways between the two diseases, with lipid metabolism playing a vital role in the cross-talk. Our findings offer insights into the shared immune mechanisms of IgAN and IBD. These common pathways, diagnostic cross-talk genes, and cell-mediated abnormal immunity may inform further experimental studies.

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Section: Discussionmentioning

confidence: 99%

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy

Yan,

Zhao,

Liu

et al. 2024

Renal Failure

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“…In specific inflammatory conditions such as diet-induced obesity and LPS-stimulated macrophage models, empagliflozin has been observed to decrease the presence of pro-inflammatory M1 macrophages by inhibiting IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 pathways, while simultaneously promoting the presence of anti-inflammatory M2 macrophages. This mechanism ultimately results in a reduction in tissue inflammation [191,192]. Furthermore, empagliflozin has shown significant inhibition of genes associated with fibrosis promotion and macrophage polarization, thereby impeding the formation of profibrotic CD206+CD68+ M2 macrophages through the regulation of mitophagy and mTOR pathways [172].…”

Section: Adoption Of Macrophage Polarization Toward M2 Phenotypementioning

confidence: 99%

Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease

Lin,

Yang,

et al. 2024

IJMS

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Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition.

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Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Chen,

Wang,

Bakker

et al. 2024

Basic Res Cardiol

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Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.

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SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression

Cited by 5 publications

References 63 publications

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy

Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

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