Ginsenoside Rg1 attenuates the inflammation and oxidative stress induced by diabetic nephropathy through regulating the PI3K/AKT/FOXO3 pathway

Abstract

Background: Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus. Ginsenoside Rg1 (Rg1) is an important active ingredient extracted from Panax ginseng. This study aimed to investigate the role and molecular mechanism of Rg1 in DN model. Methods: The mesangial cell line HBZY-1 was induced by high glucose (HG; 30 mM D-glucose). HGinduced HBZY-1 cells were treated with Rg1 (2.5, 5, 10 μmol/L). Cell viability was measured by the MTT assay. Apoptosis was detected by Hoechst staining and flow cytometry. Related proteins were measured by western blot. Reactive oxygen species (ROS) production was measured by dichlorodihydrofluorescein diacetate (DCFH-DA). Inflammatory factors and molecules associated with oxidative stress were detected by enzyme-linked immunoassay (ELISA). DN rats model were treated with 50 mg/kg/d Rg1 for 8 weeks, the histopathological changes and the expression of relevant markers were analyzed. Results: We found that Rg1 treatment markedly elevated the survival rates of HG-induced HBZY-1 cells and reduced apoptosis induced by HG. Rg1 treatment attenuated the HG-induced inflammatory response by decreasing the high levels of TNF-α, IL-1β, and IL-6. Furthermore, Rg1 treatment alleviated HGinduced oxidative stress by decreasing ROS generation, malondialdehyde (MDA), and lactate dehydrogenase (LDH) accumulation and increasing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). After Rg1 (50 mg/kg/d) treatment, the severe glomerular thylakoid hyperplasia, glomerular atrophy, tubule dermal cell exfoliation, basement membrane exposure, interstitial edema and inflammatory cell cytoplasmic infiltration were alleviated in DN rats. DN rat model treated with Rg1 (50 mg/kg/d) showed good anti-inflammatory and antioxidant activities. Rg1 treatment also increased the levels of the phosphorylation of PI3K (p-PI3K) and AKT (p-AKT) and promoted the transfer of FOXO3 from the nucleus to the cytoplasm in vitro and in vivo. Conclusions: Rg1 exhibited protective effects on DN-induced inflammatory responses and oxidative stress via regulating the PI3K/AKT/FOXO3 pathway in in vitro and in vivo. The results suggest that Rg1 may be a potential therapeutic agent for DN treatment.

Sacubitril/Valsartan Improves Progression of Early Diabetic Nephropathy in Rats Through Inhibition of NLRP3 Inflammasome Pathway

“… 21 The imbalance of oxidative status in renal tissues is manifested by elevated MDA levels, which is consistent with previous reports. 30–32 In our study, we found that DN rats accompanied by upregulation of NLRP3 inflammasome expression exhibited a significant oxidative stress state, such as elevated MDA and reduced antioxidant enzyme SOD, accompanied by altered renal tissues, consistent with previous studies, 32 considering the involvement of NLRP3 inflammasomes in the oxidative stress response in glycogenic renal tissues. In contrast, Sac treatment successfully down-regulated MDA expression by down-regulating inflammasome expression, blocking the renal oxidative stress response and reducing renal tissue damage.…”

Oxidative Stress and Ginsenosides: An Update on the Molecular Mechanisms

“…The antioxidative stress effect of 20( R )-Rg3 is related to the activation of the PI3K/AKT signaling pathway. Liu et al [ 97 ] found that ginsenoside Rg1 treatment alleviated high glucose-induced oxidative stress by decreasing ROS generation, MDA, and LDH accumulation and increasing the activities of SOD and GSH-Px. The molecular mechanism of Rg1 is considered related to the regulation of the PI3K/AKT/FOXO3 pathway.…”

Ginsenoside Rg1 ameliorates sepsis-induced acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells

“…Rg1 mitigates inflammation and oxidative stress caused by diabetic nephropathy by mediating the PI3K/AKT/FOXO3 pathway. 33 Equally importantly, ginsenoside Rg1 ameliorates LPS-induced chronic kidney injury by reducing NOX2-mediated oxidative stress 34 and effectively alleviates aldosterone-induced oxidative stress and podocyte autophagy 35 and kidney injury. 36 As acknowledged, ferroptosis is extremely associated with enhanced lipid peroxidation and overproduction of ROS.…”

“…Previous research has documented that ginsenoside Rg1 could protect against kidney injury by attenuating oxidative stress 32 . Ginsenoside Rg1 mitigates inflammation and oxidative stress caused by diabetic nephropathy by mediating the PI3K/AKT/FOXO3 pathway 33 . Equally importantly, ginsenoside Rg1 ameliorates LPS‐induced chronic kidney injury by reducing NOX2‐mediated oxidative stress 34 and effectively alleviates aldosterone‐induced oxidative stress and podocyte autophagy 35 and kidney injury 36 .…”