Cafestol ameliorates diabetic nephropathy via Keap1-Nrf2 axis activation: A novel renoprotective mechanism independent of glycemic control

Abstract

Diabetic nephropathy is an early complication of diabetes, which triggers lipotoxicity, oxidative stress, inflammation, fibrosis, and apoptosis. This study aimed to investigate the possible protective effects of Cafestol and the underlying molecular mechanisms in type 1 diabetes-induced nephropathy. One dose of streptozotocin (65 mg/kg, i.p.) was used to induce diabetes, then Cafestol was given orally at 5 and 10 mg/kg for eight weeks. In the control rats, Cafestol (10 mg/kg) did not cause any significant changes to any of the measured parameters, including 24-hour urine volume, urinary albumin, creatinine, and renal injury parameters (KIM-1, NGAL, nephrin), suggesting that Cafestol has no adverse renal effect in normal physiology. In T1DM induction rats, renal dysfunction was apparent as marked increases in urine output, enzymatic indicators of injury, inflammatory mediators (IL-6, TNF-α, ICAM-1, nuclear NF-κB), oxidative stress (MDA), and glycation markers (AGEs, sRAGEs), while there were significant decreases in antioxidant defenses (HO-1, SOD, GSH) and nuclear Nrf2 expression. Treatment with Cafestol at doses of 5 mg/kg and 10 mg/kg significantly reduced the pathological parameters when compared to T1DM alone in a dose-dependent manner. Cafestol treatment reduced glomerular and tubular injury, inhibited renal inflammation, restored oxidative balance, and improved antioxidant capacity. Cafestol treatment also reduced renal Keap1 mRNA expression and increased cytoplasmic and nuclear Nrf2 protein levels, indicating that Cafestol activates the Nrf2 pathway without altering Nrf2 mRNA expression. Further, co-administration of Brusatol, an Nrf2 inhibitor, eliminated the renal protection effects of Cafestol for all measured parameters and returned levels to T1DM alone. The results suggest that Cafestol provides substantial renal protective, anti-inflammatory, and antioxidative benefits in a model of diabetes, mainly through the activation of Nrf2. This finding suggests that Cafestol may be a novel agent to activate Nrf2, which may have implications for the treatment of DN.