Episodes of acute kidney injury (AKI) increase the risk of chronic kidney disease (CKD). Proximal tubular uptake of aristolochic acid (AA) induces aristolactam (AL)-DNA adducts, which induce a p53-mediated DNA damage response and acute tubular injury. Recurrent exposure to AA causes kidney function loss and fibrosis in humans (Balkan nephropathy), and is a model of AKI to CKD transition. SGLT2 inhibitors protect against CKD progression regardless of the presence of diabetes, however, the underlying mechanism is still unclear. Here we elucidated the effects of SGLT2 inhibition on AA-induced kidney injury. 15-week-old C57BL/6J female and male mice were administered vehicle or AA every 3 days for 3 weeks at a dose of 10 and 3 mg/kg i.p., respectively. Application of dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. Urine/plasma were collected after completion of AA injections and 3 weeks later together with kidneys (n=7-11/group). AA-induced increases in plasma creatinine and urinary albumin excretion were robustly attenuated by dapa independent of sex. These effects of dapa were associated with lower urinary levels of kidney-injury molecule 1 (KIM1, normalized to creatinine) after injection and lower kidney mRNA expression of p53 and KIM1 at harvest. Renal up-regulation of pro-inflammatory and pro-fibrotic genes as well as collagen staining by AA were likewise significantly attenuated by dapa. Dapa caused a minor numerical reduction in kidney AL-DNA adduct formation when assessed one day after a single AA injection (by ~10%; P=0.084). In conclusion, dapa attenuated the AA-induced p53-mediated DNA damage response and subsequent nephropathy. SGLT2 inhibitors may protect the kidneys by improving the tubular response to nephrotoxins.


Y.Oe: None. Y.Kim: None. V.S.Sidorenko: None. S.Kanoo: None. N.Lopez: None. H.A.Goodluck: None. V.Vallon: Research Support; NIH - National Institutes of Health, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Maze Therapeutics, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca.


National Institutes of Health (R01DK112042, R01DK132690, R01AG061296, P30DK079337)

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