The Influence of SGLT2 Inhibitors on the Immune System and Inflammatory Processes in Kidney Transplantation.
4 affiliations
- 1Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico.
- 2Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara 44340, Jalisco, Mexico.
- 3Department of Nutrigenomics, University Center of Health Services, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico.
- 4Departamento de Cirugía General, Hospital Civil de Guadalajara "Juan I Menchaca", Guadalajara 44360, Jalisco, Mexico.
Abstract
Kidney transplantation (KT) remains the optimal therapy for end-stage kidney disease (ESKD), yet long-term graft survival is limited by unremitting allograft dysfunction and non-immune treatment toxicities. Sterile inflammation primarily drives graft failure. This inflammatory process releases damage-associated molecular patterns (DAMPs). DAMPs activate pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) 2 and 4, from proximal tubule epithelial cells, endothelial compartments, and infiltrating myeloid lineages. PRR signaling and the release of pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) promote pro-inflammatory M1 macrophage polarization and accelerate interstitial fibrosis and tubular atrophy (IFTA). While maintenance immunosuppression prevents adaptive rejection, it causes severe metabolic, cardiovascular, and oncologic complications, including post-transplant diabetes mellitus, hypertension, and malignancies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (dapagliflozin, empagliflozin, canagliflozin) have emerged as novel disease-modifying, immunomodulatory adjuncts that act independently of glycemic control. SGLT2 inhibition reactivates tubuloglomerular feedback to relieve intraglomerular hypertension, blunts hyperfiltration, and reduces tubular transport workload. This alleviates cortical hypoxia, curtails mitochondrial ROS production, and activates AMP-activated protein kinase (AMPK) to suppress NF-κB and NLRP3 inflammasome assembly. SGLT2 inhibitors downregulate TLR expression, drive a phenotypic shift toward reparative M2 macrophages, reduce proteinuria, and provide sustained volume decongestion without triggering compensatory activation of the renin-angiotensin-aldosterone system. By targeting both upstream bioenergetic strain and downstream fibrotic remodeling (YAP/TAZ axis), SGLT2 inhibitors complement standard immunosuppression to protect allograft architecture, reduce cardiovascular morbidity, and improve long-term transplant outcomes.
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BibTeX
@article{garciasanchez2026influence,
title = {{The Influence of SGLT2 Inhibitors on the Immune System and Inflammatory Processes in Kidney Transplantation.}},
author = {Andrés García-Sánchez and Pablo Ortíz-Lazareno and Leonardo Pazarín-Villaseñor and Elodia Nataly Díaz-de la Cruz and Alondra Mora-Jiménez and Jorge Andrade-Sierra and Ernesto Germán Cardona-Muñoz and Sylvia Elena Totsuka-Sutto and Luis Francisco Gómez-Hermosillo and Jorge Casillas-Moreno and Tannia Isabel Campos-Bayardo and Daniel Román-Rojas and Juan Antonio Garzón-Lamarque and Alejandra Guillermina Miranda-Díaz},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198547},
url = {https://europepmc.org/article/MED/42883794},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Influence of SGLT2 Inhibitors on the Immune System and Inflammatory Processes in Kidney Transplantation.
AU - Andrés García-Sánchez
AU - Pablo Ortíz-Lazareno
AU - Leonardo Pazarín-Villaseñor
AU - Elodia Nataly Díaz-de la Cruz
AU - Alondra Mora-Jiménez
AU - Jorge Andrade-Sierra
AU - Ernesto Germán Cardona-Muñoz
AU - Sylvia Elena Totsuka-Sutto
AU - Luis Francisco Gómez-Hermosillo
AU - Jorge Casillas-Moreno
AU - Tannia Isabel Campos-Bayardo
AU - Daniel Román-Rojas
AU - Juan Antonio Garzón-Lamarque
AU - Alejandra Guillermina Miranda-Díaz
PY - 2026
DA - 2026/09/24
JO - International journal of molecular sciences
DO - 10.3390/ijms27198547
UR - https://europepmc.org/article/MED/42883794
AB - Kidney transplantation (KT) remains the optimal therapy for end-stage kidney disease (ESKD), yet long-term graft survival is limited by unremitting allograft dysfunction and non-immune treatment toxicities. Sterile inflammation primarily drives graft failure. This inflammatory process releases damage-associated molecular patterns (DAMPs). DAMPs activate pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) 2 and 4, from proximal tubule epithelial cells, endothelial compartments, and infiltrating myeloid lineages. PRR signaling and the release of pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) promote pro-inflammatory M1 macrophage polarization and accelerate interstitial fibrosis and tubular atrophy (IFTA). While maintenance immunosuppression prevents adaptive rejection, it causes severe metabolic, cardiovascular, and oncologic complications, including post-transplant diabetes mellitus, hypertension, and malignancies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (dapagliflozin, empagliflozin, canagliflozin) have emerged as novel disease-modifying, immunomodulatory adjuncts that act independently of glycemic control. SGLT2 inhibition reactivates tubuloglomerular feedback to relieve intraglomerular hypertension, blunts hyperfiltration, and reduces tubular transport workload. This alleviates cortical hypoxia, curtails mitochondrial ROS production, and activates AMP-activated protein kinase (AMPK) to suppress NF-κB and NLRP3 inflammasome assembly. SGLT2 inhibitors downregulate TLR expression, drive a phenotypic shift toward reparative M2 macrophages, reduce proteinuria, and provide sustained volume decongestion without triggering compensatory activation of the renin-angiotensin-aldosterone system. By targeting both upstream bioenergetic strain and downstream fibrotic remodeling (YAP/TAZ axis), SGLT2 inhibitors complement standard immunosuppression to protect allograft architecture, reduce cardiovascular morbidity, and improve long-term transplant outcomes.
SN - 1422-0067
ER -