Semaglutide/Acarbose combination protects against diabetic nephropathy in rats; a novel insight into modulation of Nrf-2/HO-1& TGF-β/Smad pathways.

BACKGROUND: Diabetic nephropathy (DN) is a clinical condition characterized by progressive decline in kidney function, with persistent albuminuria. DN pathophysiology involves chronic hyperglycaemia, oxidative stress, glomerulosclerosis, interstitial fibrosis and apoptosis. Semaglutide (S) and acarbose (A), antidiabetic drugs with different mechanisms, were explored in this study in a combination regimen to treat experimentally-streptozotocin (STZ)-induced DN in a rat model. METHODS: Fifty-six male rats were divided into 7-groups. Except for the non-diabetic negative control rats (group-I), all other groups had DN induced by an I·P injection of STZ. In group-II & III, STZ-diabetic rats did not receive any medication. Diabetic rats in group-IV (DN/S) and group-V (DN/A), administered semaglutide (30 nmol/kg/week/S.C), and acarbose (50 mg/kg/day/orally), respectively, for 4-weeks. Group-VI [DN/S/A(HD)], administrated both drugs. In group-VII [DN/S/A(LD)], diabetic rats administrated semaglutide (20 nmol/kg/week/S·C) and acarbose (30 mg/kg/day/orally) for 4-weeks. Serum glucose, creatinine/KIM-1 levels and albuminuria were measured. Renal; Nrf-2/HO-1 immunoreactivities, NF-κB/TNF-α/IL-10 levels, TGF-β1/Smad 2/3, and cl-caspase-3/Bax/Bcl-2 expressions were assessed. RESULTS: Compared to solo treatment of either drug, semaglutide/acarbose combination (in high and low doses) regenerated the histopathological features and restored kidney functions through stimulation of Nrf-2/HO-1, attenuation of inflammatory signals via modulation of NF-κB/TNF-α/IL-10 levels. Fibrosis and apoptosis were mitigated by suppression of the TGF-β1/Smad and overall reduction in Bax/Bcl-2 ratio, respectively. CONCLUSION: The combination of semaglutide/acarbose is more effective than the solo treatment with either drug, even upon using lower doses in the combination, suggesting a synergistic effect. The study unveiled a potential therapeutic regimen for DN, that was not evaluated before.