Figure 8.

The mechanism of the protective effect of fenofibrate against diabetic nephropathy. Oxidative stress is a key pathogenic factor in the development of DN. Under diabetic conditions, glucose metabolism is impaired and excessive amounts of reactive oxygen species (ROS) are produced, which accumulate in the kidney and induce oxidative stress. Oxidative stress causes renal cellular injury and apoptosis, followed by inflammation and fibrosis, which ultimately leads to renal dysfunction. Our previous study showed that FF-induced renal protection from diabetes is mediated through an upregulation of FGF21, and this in turn stimulates Akt/GSK-3β/Fyn-mediated activation of the Nrf2 anti-oxidative pathway. The present study reveals that the protective effect of FF/FGF21 on DN is dependent on Akt2. The activation of the Akt2/GSK-3β/Fyn pathway increases the nuclear translocation of Nrf2 by inhibiting the nuclear accumulation of Fyn, and induces antioxidant gene expression. However, AMPK activation can also alleviate the metabolic defects, and both pathways prevent renal oxidative stress, inflammation, and remodeling.