Combined dapagliflozin and pioglitazone therapy in diabetic nephropathy: no added benefit beyond monotherapy in inflammation and fibrosis

Diabetic nephropathy (DN) is currently a leading cause of end-stage renal disease. Both dapagliflozin and pioglitazone have shown protective effects on organ damage in diabetes, even beyond their blood glucose-lowering properties. This study aimed to assess whether the simultaneous activation of PPARγ and inhibition of SGLT2 cotransporters provide additive protection against inflammation and fibrosis which are highly engaged in the progression of DN in experimental type 1 diabetes mellitus. Diabetes was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.), and the animals received daily chow containing dapagliflozin (10 mg/kg), pioglitazone (12 mg/kg), or their combination. Six weeks after streptozotocin administration, molecular, histological and immunohistochemical analyses were performed in the excised kidneys. In the kidneys of diabetic rats, disruption of renal function markers was accompanied by increased macrophage infiltration and collagen deposition. Both pioglitazone and dapagliflozin decreased proinflammatory markers expression (IL1b, IL6, Cox2, Tnfα) and CD68-positive areas. Both monotherapies positively modulated Tgfβ, HGF and Agtr1 expression, leading to fibrosis reduction and morphological normalisation. Similarly to pioglitazone, the combined therapy reduced α-SMA-positive areas. Despite an additive antihypertensive effect, the combination maximally reached the effect of the monotherapies in other measured parameters. Overall, both dapagliflozin and pioglitazone are renoprotective in monotherapy, but their combination does not provide additional benefits in reducing inflammation, fibrosis or restoring kidney function.