Diabetic nephropathy (DN) is a globally widespread complication of diabetes mellitus (DM). Research indicates that pioglitazone and linagliptin mitigate the risk of DN by reducing inflammation, oxidative stress, and fibrosis. The role of tamsulosin in DN is less studied, but it may contribute to reducing oxidative stress and inflammatory responses. The protective effects of combining pioglitazone, linagliptin, and tamsulosin on the kidneys have scarcely been investigated. This study examines the individual and combined effects of these drugs on DN in Wistar rats. Diabetic rats were treated with tamsulosin, pioglitazone, and linagliptin for six weeks. We assessed food and water intake, estimated glomerular filtration rate (eGFR), histological markers, urea, creatinine, glucose, NF-κB, IL-1, IL-10, TGF-β, and Col-IV using immunofluorescence and qPCR. The DN group exhibited hyperglycaemia, reduced eGFR, and tissue damage. Tamsulosin and linagliptin improved eGFR, decreased urinary glucose, and repaired tissue damage. Pioglitazone and its combinations restored serum and urinary markers and reduced tissue damage. Linagliptin lowered serum creatinine and tissue injury. In conclusion, tamsulosin, linagliptin, and pioglitazone demonstrated renoprotective effects in DN.

Diabetic nephropathy (DN) is a consequence of diabetes mellitus (DM), in which hyperglycemia triggers osmotic and oxidative stress and activates inflammatory pathways. These processes damage kidney cells, with mesangial cells (MCs) undergoing mesangial expansion. Antihyperglycemic drugs prevent the progression of renal disease. Although tamsulosin is not conventionally used for the treatment of DN, its previously reported anti-fibrotic and anti-inflammatory effects in liver and lung injury models suggest that it may exert renoprotective actions like those of pioglitazone, which has also been shown to improve cellular carbohydrate and lipid metabolism. MCs were exposed to 20 mM glucose medium and treated with either 50 nM tamsulosin or 100 nM pioglitazone. Subsequently, cell proliferation, inflammatory markers (NF-κB, IL-1β, IL-17), fibrogenic markers (TGF-β, collagen I), oxidative stress parameters (NRF2, superoxide), and indicators of mesangial activation (α-SMA, rhodamine–phalloidin) were assessed in vitro. Both treatments reduced cellular proliferation and hypertrophy, attenuated the release of reactive oxygen species (ROS), decreased IL-17 and α-SMA expression, and reduced mesangial activation and hypertrophy. In an in vivo model of DN in Wistar rats, both treatments decreased mesangial cell activation and expansion. In conclusion, tamsulosin and pioglitazone exert anti-fibrogenic and anti-inflammatory effects in MCs exposed to HG, thereby limiting mesangial activation and expansion.