A recent study conducted by researchers from Xuzhou Medical University has shed light on a potential treatment for diabetic nephropathy (DN), a severe complication of diabetes mellitus that can lead to kidney failure. The study focused on the effects of tiliroside, a flavonoid found in Potentilla chinensis, on mesangial cells exposed to high glucose levels, mimicking the environment of DN.
Oxidative stress, caused by the overproduction of reactive oxygen species (ROS), plays a significant role in the development of DN. The researchers found that tiliroside inhibited the proliferation of mesangial cells induced by high glucose, suggesting its potential as a therapeutic agent for DN. Moreover, tiliroside was found to reduce ROS production and decrease levels of malondialdehyde (MDA), a marker of oxidative stress, in mesangial cells.
Renal fibrosis, characterized by the accumulation of extracellular matrix (ECM) proteins, is another hallmark of DN. The study revealed that tiliroside suppressed the secretion of TGF-β1 and connective tissue growth factor (CTGF), two fibrotic factors involved in the pathogenesis of DN. Additionally, tiliroside reduced the levels of ECM proteins, such as collagen IV, fibronectin, and laminin, suggesting its potential to prevent renal fibrosis.
The researchers also investigated the mechanism of action of tiliroside and found that it activated a transcription factor called nuclear factor erythroid 2-related factor 2 (Nrf2). This activation led to an increase in the levels of Nrf2 in both the cytosol and the nucleus. Tiliroside also enhanced the binding of Nrf2 to antioxidant response elements (ARE) in the promoters of target genes, upregulating genes involved in antioxidant defense. Knockdown of Nrf2 abolished the effects of tiliroside on oxidative stress and ECM accumulation, confirming the importance of Nrf2 activation in tiliroside’s effects.
Furthermore, the study revealed that tiliroside disrupted the interaction between Nrf2 and Kelch-like ECH-associated protein 1 (Keap1), a protein that regulates Nrf2 activity. Molecular docking studies suggested that tiliroside acts as an electrophile, reacting with critical cysteine residues on Keap1. This prevents the degradation of Nrf2 and promotes its nuclear translocation, further enhancing its antioxidant effects.
These findings provide valuable insights into the potential use of tiliroside as a natural compound for the treatment of DN. By inhibiting mesangial cell proliferation, reducing oxidative stress, and attenuating ECM accumulation, tiliroside shows promise in addressing the underlying mechanisms of DN. The activation of Nrf2 and the disruption of the Keap1-Nrf2 complex by tiliroside offer new avenues for the development of natural Nrf2 activators and phytochemical-based treatments for DN. Overall, these findings provide hope for improved management of this severe diabetic complication.