Timing-dependent renal protection of dapagliflozin in endotoxemic diabetic mice by real-time GFR and biomarkers.

introductionType 2 diabetes mellitus (T2DM) increases susceptibility to sepsis-associated acute kidney injury (SA-AKI). While guidelines support chronic sodium-glucose cotransporter 2 (SGLT2) inhibitor use in T2DM, their efficacy and optimal intervention timing in acute sepsis remain unclear. We hypothesized that this efficacy is timing-dependent. To test this, we utilized a T2DM mouse model subjected to graded lipopolysaccharide (LPS) challenges as a clinically relevant surrogate for sepsis. Notably, to precisely capture the longitudinal and dynamic trajectory of renal function, we incorporated continuous real-time transcutaneous glomerular filtration rate (tGFR) monitoring. We evaluated the SGLT2 inhibitor dapagliflozin (DAPA) across three regimens representing distinct clinical scenarios: preventive (pre-LPS only, modeling prior chronic use), therapeutic (initiated post-LPS, modeling de novo intensive care initiation), and whole-course (continuous administration, modeling treatment continuation).

resultsFollowing LPS challenge, T2DM exacerbated renal dysfunction across all doses and impaired endogenous functional recovery. High-resolution real-time tGFR tracking and subsequent biomarker analyses revealed that the renoprotective effect of DAPA was dependent on the timing of intervention. In moderate endotoxemia, both therapeutic and whole-course regimens were superior to the preventive regimen. Compared to preventive administration alone, initiating or continuing treatment during the acute insult (therapeutic and whole-course regimens) more effectively preserved early glomerular filtration rate (GFR) trajectories, attenuated the rise in tubular injury markers, and promoted histological repair.

conclusionsSupported by dynamic renal function monitoring, this study demonstrates that DAPA provides significant renoprotection in a preclinical T2DM model of endotoxemia-associated acute kidney injury. This efficacy is closely associated with the timing of intervention, with greater protective effects observed when treatment is initiated during or maintained after the acute endotoxemic challenge. These preclinical findings suggest that intervention timing could be a key determinant of SGLT2 inhibitor efficacy, providing a scientific rationale for evaluating the prompt initiation or continuation of this therapy in diabetic patients presenting with acute sepsis.