Sodium glucose co-transporter 2 inhibitor prevents nephrolithiasis in non-diabetes by restoring impaired autophagic flux.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) offer significant cardiovascular and kidney protection, independent of diabetes mellitus (DM). Recent cohort studies also suggest that SGLT2i can decrease the risk of nephrolithiasis in patients with DM. We aimed to use both animal models and human data to investigate whether SGLT2i can prevent nephrolithiasis and explored autophagy as a possible mechanism. METHODS: We utilised SGLT2i, dapagliflozin (DAPA), on a glyoxylate (GOX)-induced calcium oxalate (CaOx) nephrolithiasis non-DM mouse model to test whether SGLT2i inhibited CaOx stone formation through modulating autophagy. Moreover, the clinical data retrieved from the National Health Insurance Research Database was analysed to confirm the findings from animal models. FINDINGS: DAPA increased urine citrate, magnesium, pH, and decreased oxalate, effectively inhibiting CaOx stones in GOX mice. While autophagy was increased in the kidneys of GOX mice, as demonstrated by upregulated AMP-activated protein kinase (AMPK) and increased LC3B conversion; impaired autophagic flux was indicated by p62 accumulation. DAPA improved autophagy by downregulating mammalian target of rapamycin (mTOR), AMPK, and restoring autophagic flux. Rapamycin co-treatment preserved DAPA's nephrolithiasis inhibition, while hydroxychloroquine (HCQ) co-treatment abolished it. Finally, cohort data confirmed that SGLT2i reduced nephrolithiasis risk, but this protective effect disappeared if HCQ had been used within the prior year, suggesting that HCQ may compromise SGLT2i's protection against nephrolithiasis. INTERPRETATION: SGLT2i, DAPA, inhibits nephrolithiasis by restoring impaired autophagic flux, and co-administration with autophagy inhibitor, HCQ, compromises SGLT2i's protection. FUNDING: This research was funded by grants from the National Science and Technology Council, Taiwan (110-2314-B-006-023, 110-2320-B-006-017MY3, and 112-2314-B-006-058) and the research grants (NCKUH-11202005, -11210020) from the National Cheng Kung University Hospital, Tainan, Taiwan.