Renal Protection of HWL-088and ZLY-032, Two Dual GPR40/PPARδ Agonists, in Adenine-Induced Renal Fibrosis Model

This research examined the potential of novel GPR40/PPARδ dual agonists, HWL-088 and ZLY-032, to protect the kidneys in a mouse model of adenine-induced renal fibrosis. Mice were given a diet containing 0.25 % adenine to develop renal fibrosis and then received different dosages of HWL-088 or ZLY-032. After being euthanized, tissue and serum samples were collected for morphological, histological, and molecular examination. Compared to the control group, mice fed adenine showed an increase in kidney-to-body weight ratio, serum creatinine, and urea levels. Hematoxylin and eosin staining revealed alleviated glomerulosclerosis, tubular dilation, and inflammatory cell infiltration in mice treated with HWL-088 or ZLY-032. Furthermore, Masson staining and immunohistochemistry demonstrated that these dual agonists protected against renal interstitial fibrosis and inflammation, corroborated by decreased expression levels of fibrosis-related proteins (TGF-β, Collα1, TIMP-1) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Accordingly, it can be inferred that GPR40/PPARδ dual agonists HWL-088 and ZLY-032 could yield significant renoprotective effects by inhibiting inflammation and fibrosis. Overall, these results may contribute to the development of novel therapeutic strategies for renal fibrosis.