EFFECT OF SGLT2 INHIBITORS ON MARKERS OF PYROPTOSIS AND RENAL INFLAMMATION IN DIABETIC NEPHROPATHY: A SYSTEMATIC REVIEW

Diabetic nephropathy is the leading cause of end-stage chronic kidney disease. Despite standard therapies, a residual risk persists that is attributable to sterile inflammation and cell loss. Among the mechanisms of regulated cell death, pyroptosis stands out as a lytic process mediated by the activation of the NLRP3 inflammasome and caspase-1. This pathway induces the cleavage of gasdermin D (GSDMD), leading to the insertion of transmembrane pores and the massive release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), thereby accelerating podocyte depletion and tubulointerstitial fibrosis.
A systematic review was conducted in PubMed (2021–2026) to evaluate the preclinical and clinical evidence regarding the modulation of pyroptosis by SGLT2 inhibitors (empagliflozin, dapagliflozin, and canagliflozin).
The data show that SGLT2 inhibitors suppress NLRP3 assembly by reducing mitochondrial reactive oxygen species, regulating the ROS/TXNIP pathway, stimulating AMPK, and restoring podocyte mitophagy. This inhibition blocks caspase-1 activation and the translocation of the cytotoxic GSDMD-N fragment to the plasma membrane, thereby preventing cell lysis and the secretion of IL-1β and IL-18. As a result, essential podocyte cytoskeletal proteins (nephrin and synaptopodin) are preserved, tubular senescence is reduced, and interstitial fibrosis is attenuated, which clinically correlates with a sustained reduction in proteinuria and the preservation of renal function.
In conclusion, the inhibition of pyroptosis constitutes an autonomous cytoprotective mechanism of SGLT2 inhibitors that goes beyond their hemodynamic properties, emerging as a primary therapeutic target against diabetic kidney damage.