Wogonin Alleviates Kidney Tubular Epithelial Injury in Diabetic Nephropathy by Inhibiting PI3K/Akt/NF-κB Signaling Pathways

Abstract

Introduction: Kidney tubular epithelial injury is one of the key factors in the progression of diabetic nephropathy (DN). Wogonin is a kind of flavonoid, which has many pharmacological effects, such as anti-inflammation, anti-oxidation and anti-fibrosis. However, the effect of wogonin in renal tubular epithelial cells during DN is still unknown. Materials and Methods: STZ-induced diabetic mice were given doses of wogonin (10, 20, and 40 mg/kg) by intragastric administration for 16 weeks. The metabolic indexes from blood and urine and pathological damage of renal tubules in mice were evaluated. Human tubular epithelial cells (HK-2) were cultured in high glucose (HG) condition containing wogonin (2μM, 4μM, 8μM) for 24 h. Tubular epithelial cell inflammation and autophagic dysfunction both in vivo and in vitro were assessed by Western blot, qRT-PCR, IHC, and IF analyses. Results: The treatment of wogonin attenuated urinary albumin and histopathological damage in tubulointerstitium of diabetic mice. We also found that wogonin down-regulated the expression of pro-inflammatory cytokines and autophagic dysfunction in vivo and in vitro. Molecular docking and Cellular Thermal Shift Assay (CETSA) results revealed that mechanistically phosphoinositide 3-kinase (PI3K) was the target of wogonin. We then found that inhibiting PI3K eliminated the protective effect of wogonin. Wogonin regulated autophagy and inflammation via targeting PI3K, the important connection point of PI3K/Akt/ NF-κB signaling pathway. Conclusion:Our study is the first to demonstrate the novel role of wogonin in mitigating tubulointerstitial fibrosis and renal tubular cell injury via regulating PI3K/Akt/NF-κB signaling pathway-mediated autophagy and inflammation. Wogonin might be a latent remedial drug against tubular epithelial injury in DN by targeting PI3K.

Protective role of wogonin following traumatic brain injury by reducing oxidative stress and apoptosis via the PI3K/Nrf2/HO‑1 pathway

“…The mechanism of wogonin in the treatment of lung cancer involves the PI3K/Akt signaling pathway ( 45 ). Wogonin reduces renal tubular damage by regulating autophagy and inflammation mediated by PI3K/Akt/NF-κB signaling pathway ( 13 ). For nervous system and brain diseases, wogonin has been found to inhibit the phosphorylation of Akt and NF-κB and delay the growth of gliomas ( 46 ).…”

“…Wogonin has a variety of biological activities including anti-inflammatory, antioxidant and anti-tumor properties ( 10 - 12 ). For example, wogonin alleviates tubulointerstitial fibrosis and kidney tubular epithelial injury through the PI3K/Akt/NF-κB signaling pathway that mediates autophagy and inflammation in diabetic nephropathy ( 13 ). In a cell model of lung injury, wogonin prevents apoptosis of injured lung cells by inhibiting the expression of the Bcl-2 antagonist of cell death (BAD) gene and subsequent activation of cleaved caspase-3 through the PI3K/AKT pathway ( 14 ).…”

Deciphering the Mechanism of YuPingFeng Granules in Treating Pneumonia: A Network Pharmacology and Molecular Docking Study

“…These protective effects are through the reduction of caspase-3, TNF, and toll-like receptor 2 expression [ 54 ]. In vivo experiments in mice suggest that wogonin inhibits the PI3K/Akt/NF- κ B signaling pathway, reducing autophagy and inflammation, and then reducing renal tubular cell damage [ 55 ].…”

Scutellaria baicalensis georgi is a promising candidate for the treatment of autoimmune diseases

“…Frontiers in Pharmacology frontiersin.org pro-inflammatory cytokine production, which is likely to be associated with its inhibitory effect on osteopontin expression through enhancing PPARα activity (Zhang Y. M. et al, 2015;Liu et al, 2022). Besides, WGI's ameliorative effect on STZ-induced symptoms like urinary albumin, histopathological damage and renal inflammation and fibrosis was related to its negative regulation on PI3K/Akt/NF-κB and TGF-β1/Smad3 (Zheng et al, 2020;Lei et al, 2021). Apart from T1DM secondary renal dysfunction, WGI was announced to alleviate diabetic cardiomyopathy through enhancing SOD1/2 and CAT while attenuating productions of ROS/MDA and proinflammatory cytokines (Khan et al, 2016).…”