Mus musculus Raw sequence reads
Diabetic nephropathy (DN), a diabetic complication, is characterized by microcirculation disorders, chronic inflammation, and glomerular fibrosis, ultimately culminating in renal failure. Increasing evidence indicates that the complex interplay between host and intestinal microbiota is pathophysiologically involved in DN. Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control underlying the therapeutic impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating the mechanisms by which dapagliflozin mitigated DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and strengthened gut permeability in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and db/db mice without affecting blood glucose levels. These effects were associated with significantly altering the gut microbial composition and function. Resident microbiota eradication abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin caused significant changes in microbial metabolites in DN mice, particularly decreased levels of argininosuccinic acid (ASA), palmitic acid (PA), and increased levels of S-allylcysteine (SAC). ASA and PA triggered renal inflammation and fibrosis in HK-2 cells, while SAC restored renal damage and modified the microbial composition similar to dapagliflozin treatment in DN mice. Notably, Muribaculaceae and Desulfovibrionaceae were identified to be correlated with alleviated DN-associated renal dysfunction by both low and high-dose dapagliflozin treatments in DN mice. These findings contribute to establishing a theoretical foundation for the potential application of dapagliflozin in the management of DN by targeting the gut microbiota