Renoprotective Effects of Phloretin and TUDCA via Simultaneous Inhibition of TLR4/MyD88/NF-κB and BiP/PERK/CHOP Pathways in AKI Under Diabetic Condition.

The diabetic milieu increases the chances of acute kidney injury (AKI) progression. During AKI, activation of the inflammatory response via Toll-like receptor 4 (TLR4) and endoplasmic reticulum (ER) stress progress in kidney dysfunction. Moreover, emerging evidence suggests a functional interplay between TLR4 signaling and ER stress in kidney disease. However, the effect of simultaneous inhibition of these mechanisms has not yet been studied in AKI under diabetic settings. In this study, we investigated the renoprotective effect of Phloretin-TLR4 inhibitor and Tauro ursodeoxycholic acid (TUDCA)-ERS inhibitor in AKI under diabetic condition. Using a bilateral ischemia-reperfusion injury (BIRI) model in streptozotocin-induced diabetic rats and a high glucose cultured sodium azide-induced injury model in NRK52E cells, we evaluated the effects of both agents administered alone and in combination. In rats, phloretin at 50 mg/kg/p.o. and TUDCA at 400 mg/kg/p.o. alone and in combination were administered for 5 days before surgery, while in NRK52E cells, both drugs were given 24 h before hypoxia. Pretreatment with phloretin and TUDCA significantly attenuated renal dysfunction, preserved tissue architecture, and reduced markers of inflammation and apoptosis (p < 0.05). Mechanistic analysis revealed that phloretin suppressed the TLR4/MyD88/NF-κB signaling pathway, while TUDCA inhibited ER stress via the BiP/PERK/CHOP axis. Notably, combination therapy exhibited a synergistic effect (p < 0.05), offering superior renoprotection compared to monotherapy. Our findings suggest that targeting both TLR4-induced inflammation and ER stress simultaneously offers a promising therapeutic strategy for mitigating AKI in diabetic settings and may pave the way for novel combination treatments in diabetic kidney disease.