Abstract
Diabetic nephropathy (DN) is a chronic diabetic microvascular complication. Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN.
Highlights
In China, there are an estimated 110 million people with diabetes, accounting for approximately 11% of the population [1]
This study investigated the mechanism of WJ-39 in diabetic nephropathy (DN) by using a streptozotocin(STZ-) induced DN rat model and rat mesangial cells (RMCs) cultured under high glucose (HG) conditions
Renal lesions and fibrosis were observed in the periodic acid-Schiff (PAS)- and Masson’s trichrome-stained and Transmission Electron Microscopy (TEM) images of DN rat kidneys. We found that both mesangial matrix index and percentage fibrosis were considerably lower in DN rats treated with WJ-39 (Figures 2(g)–2(i))
Summary
In China, there are an estimated 110 million people with diabetes, accounting for approximately 11% of the population [1]. Abundant evidence suggests that there is cross talk between the Nrf and nuclear factor-kappa B (NF-κB) pathways, which activates the transcription of genes that produce inflammatory cytokines [6, 7]. In DN, TGF-β1 stimulates the synthesis and excessive deposition of extracellular matrix (ECM) components via different signaling pathways (e.g., Smad), which lead to the thickening of the glomerular basement membrane and mesangial expansion [14, 15]. These pathways are activated and participate in the process of DN through close cross talk and mutual reinforcement. This study investigated the mechanism of WJ-39 in DN by using a streptozotocin(STZ-) induced DN rat model and rat mesangial cells (RMCs) cultured under high glucose (HG) conditions
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