Cinnamic acid ameliorates diabetic nephropathy in rats via Nrf2 activation and inflammation modulation

Abstract

This study investigates the therapeutic effects of cinnamic acid (CA) on diabetic nephropathy (DN) and elucidates its mechanisms involving Nrf2 activation and NF-κB suppression. Type 2 diabetes mellitus (T2DM) was induced in Wistar rats through a high-fat diet followed by streptozotocin administration. Rats were assigned to each of the six groups: control, control + CA (40 mg kg⁻¹), T2DM, T2DM + CA (20 mg kg⁻¹), T2DM + CA (40 mg kg⁻¹), and T2DM + CA (40 mg kg⁻¹) with brusatol (an Nrf2 inhibitor; 2 mg per kg per twice per week). Over 8 weeks, we assessed metabolic parameters, serum lipid profiles, renal function, oxidative stress markers, and kidney histology. CA did not significantly affect the body weight or insulin levels in T2DM rats. Nevertheless, it notably reduced the fasting glucose levels and improved the renal function, as evidenced by reductions in serum creatinine and urinary albumin levels. CA treatment significantly decreased the expression of renal inflammatory markers TNF-α, IL-6, and nuclear NF-κB in the kidneys of T2DM rats. Furthermore, CA reduced oxidative stress, as demonstrated by the lower MDA levels and elevated antioxidant marker levels (GSH, SOD, and HO-1) in the kidneys of both control and T2DM rats. CA treatment increased the nuclear Nrf2 levels and decreased the transcription and cytoplasmic Keap1 levels, with the levels of these effects being dose-dependent between 20 and 40 mg kg⁻¹. The addition of brusatol reversed the beneficial effects of CA, underscoring the pivotal role of Nrf2 in mediating CA's protective actions. In conclusion, CA ameliorates renal dysfunction and mitigates oxidative stress and inflammation in T2DM rats via a hypoglycemic effect and activation of the Nrf2 pathway.