Sodium glucose cotransporter 2 inhibition does not improve active lupus nephritis in MRLlpr/lpr mice

Sodium glucose cotransporter 2 inhibitors (SGT2i) have delayed the progression of chronic kidney disease with or without diabetes. However, its effect in active glomerulonephritis such as lupus nephritis (LN) is unknown. Here, we tested the effect of the SGLT2i empagliflozin (EMP) in MRLlpr/lpr mice, a model of spontaneous systemic lupus erythematosus with active LN.

Female MRLIpr/lpr mice were treated with 10 mg/kg/day of the EMP for four weeks. To better mimic the patient setting, MRLIpr/lpr mice were randomly assigned to EMP or untreated control group between weeks nine and 13 once the signs of active LN appeared. Proteinuria levels over 100 mg/dl (++ in reactive strips) or lymphadenopathy in minimum two bilateral sites (cervical, branchial or inguinal) with proteinuria over 30mg/dl were considered as signs of an active LN. Lymphadenopathy, body weight, water and food intake were monitored weekly. Blood glucose was measured bi-weekly, while glomerular filtration rate and albumin-to-creatinine ratio were obtained at the beginning and at the end of the experiment.

EMP treatment increased glycosuria and water intake in MRLlpr/lpr mice, but did not affect blood glucose levels, body weight, or food intake. After four weeks of treatment, EMP did not alter glomerular filtration rate, albuminuria, histological glomerular IgG deposits, activity or chronicity indexes of LN, or interstitial fibrosis in MRLlpr/lpr mice.

Our results indicate that EMP does not affect proteinuria or kidney excretory function nor signs of lupus in MRLlpr/lpr mice with active LN. This suggests that SGLT2i may not affect LN activity, and they should be, rather, considered to target the chronic kidney disease aspect of LN to prevent further nephron loss.