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Dapagliflozin mitigates hypoxia-induced metabolic stress, kidney tubular cell death and fibrosis

Minakawa, A.; El Saghir, J.; Berthier, C. C.; Lasse, M.; Maity, S.; Baek, J.; Billing, A.; Fermin, D.; He, C.; Eichinger, F.; Hartman, J.; Nair, V.; Fischer, M.; Vega-Warner, V.; Alakwaa, F.; Godfrey, B.; McCown, P. J.; Menon, R.; Demir, F.; Pennathur, S.; Sharma, K.; Schaub, J.; Rinschen, M.; Kretzler, M.; Harder, J.

2025-12-16 cell biology
10.64898/2025.12.13.693777 bioRxiv
Show abstract

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) slow progression of kidney disease but therapeutic mechanisms remain elusive. Here we report the beneficial effect of dapagliflozin on hypoxia-mediated kidney tubular epithelial cell injury, a contributing factor to kidney disease progression, using a human pluripotent stem cell (hPSC)-derived hypoxic kidney organoid model. Hypoxic organoids showed increased expression of Hypoxia Inducible Factor (HIF)-associated transcriptional targets, decreased tricarboxylic acid (TCA) cycle metabolites and mitochondrial {beta}-oxidation protein expression, and activated unfolded protein response. A transcriptional signature derived from hypoxic organoids 1) identified a subgroup of individuals whose kidney disease subsequently progressed, and 2) correlated with worse tubular injury. Dapagliflozin enhanced mitochondrial stress response resulting in reversed hypoxia-induced tubular epithelial cell apoptosis, reactive oxygen species (ROS) accumulation, and organoid fibrosis. These results indicate that dapagliflozin may contribute to improved kidney disease outcomes by attenuating hypoxia-induced metabolic stress-mediated tubular epithelial cell injury.

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