Ginsenoside-Rg1 Protects against Renal Fibrosis by Regulating the Klotho/TGF-β1/Smad Signaling Pathway in Rats with Obstructive Nephropathy

Abstract

Ginsenoside-Rg1 (G-Rg1) is an agent isolated from Panax ginseng that exerts anti-fibrotic effects; however, the mechanism is still unclear. Herein, we investigated whether G-Rg1 administration can mitigate or reverse unilateral ureteral obstruction (UUO)-induced renal fibrosis by regulating the Klotho/transforming growth factor (TGF)-β1/Smad signaling pathway in rats. Sprague-Dawley male rats were subjected to UUO, and rats in the treatment group were administered G-Rg1 or G-Rg1 plus Klotho short hairpin RNA interference (shRNA), while rats in the control and model groups were administered vehicle for 14 d. Epithelial-mesenchymal transition (EMT) biomarkers and Klotho/TGF-β1 signaling molecules were examined by immunohistochemistry, quantitative real-time PCR and Western blotting. Immunohistochemistry showed that UUO induced increased pro-fibrotic TGF-β1 expression, overexpression of the mesenchymal marker, α-smooth muscle actin (α-SMA), and suppression of the epithelial marker, E-cadherin. Moreover, Western blotting analysis indicated that UUO promoted TGF-β1 and phosphorylated Smad3 (p-Smad3) expression (p<0.01), but blocked Klotho and Smad7 expression (p<0.01). After G-Rg1 administration, the UUO-induced TGF-β1 and p-Smad3 expression was suppressed (p<0.01), whereas the reduced Klotho and Smad7 expression was reversed (p<0.05), followed by amelioration of the EMT process. Intriguingly, the G-Rg1 effects were largely abrogated by Klotho knockdown. Furthermore, Klotho expression was upregulated by G-Rg1 treatment at the mRNA and protein levels. Our results suggest that G-Rg1 may be beneficial for ameliorating renal fibrosis by targeting Klotho/TGF-β1/Smad signaling in UUO rats.

Ginseng increases Klotho expression by FoxO3-mediated manganese superoxide dismutase in a mouse model of tacrolimus-induced renal injury

“…However, ginseng extracts contain multiple functional constituents, making it important to identify the key components involved directly in Klotho induction. Unfortunately, little is known regarding the effect of ginsenoside components, except Rg1, on Klotho signaling in kidney diseases [30]. Therefore, we examined which of the main ginsenosides of KRGP, e.g.…”

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

“…Another natural product that exhibits anti-fibrotic effects is Ginsenoside-Rg1 of Panax ginseng. In rat models, it has been observed that it mitigates the EMT by suppressing TGF-β1 signaling and by upregulating Klotho and Smad7 expression (Li N. et al, 2018;Li S. et al, 2018). Finally, administration of asperulosidic acid, an iridoid glycoside isolated from Hedyotis diffusa, provided various beneficial effects in an unilateral ureteral obstruction model and it also protects from renal interstitial fibrosis, by reducing the level of inflammatory proteins and by downregulating TGF-β1 signaling (Xianyuan et al, 2019).…”

Ginsenoside Rg1 attenuates arsenic-induced mice nephrotoxicity via the activated HO-1/mTOR-associated apoptosis or autophagy signaling

“…and Rg1 shows its anti-apoptosis functions involved in the regulation of mitochondrial apoptosis pathway-mediated B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase-3 [22]. In particular, Rg1 ameliorates renal fibrosis involved in the regulation of the Klotho/TGF-β1/Smad signaling pathway in rats with obstructive nephropathy [23]; The renoprotection mechanism of Rg1 in a mouse subacute damage model is attributed to alleviate oxidative stress injury in kidney [24]. In our study, the intervention with Rg1 showed a significant renoprotective role by the attenuations of oxidative stress, apoptosis and autophagy influx in kidney compared with SA exposure group, characterized as the upregulations of antioxidants GSH, HO-1 or mTOR signals, while the downregulations of pro-apoptotic Caspase-3, Bax, and autophagy-related biomarkers Beclin-1, ULK1, or LC3-B in kidney.…”