Ginsenoside Rb1 Ameliorated Bavachin-Induced Renal Fibrosis via Suppressing Bip/eIF2α/CHOP Signaling-Mediated EMT

Abstract

The nephrotoxicity of Fructus Psoraleae, an effective traditional Chinese medicine for vitiligo treatment, has been reported. As one of the main toxic components in Fructus Psoraleae, bavachin (BV) was considered to be related to Fructus Psoraleae-caused adverse outcomes, but the direct evidence and molecular mechanism underlying BV-induced nephrotoxicity are not well elucidated. Therefore, this study was designed to confirm whether BV would cause toxic effects on the kidney and explore the possible mode of action. Our results demonstrated that days’ treatment with 0.5 μM BV indeed caused obvious renal fibrosis in the zebrafish kidney. The obvious E- to N-cadherin switch and the expressions of proteins promoting epithelial–mesenchymal transition (EMT) were observed in BV-treated human renal tubular epithelial and zebrafish kidneys. In addition, elevated reactive oxygen species (ROS) levels and Bip/eIF2α/CHOP-mediated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were caused by BV, both of which could be reversed by ROS scavenger N-acetyl-L-cysteine (NAC). Also, blocking ER stress-caused cytoplasmic Ca2+ overload with 4-PBA notably alleviated BV-induced alterations in key molecular events related to EMT and renal fibrosis. Furthermore, of the natural compounds subjected to screening, ginsenoside Rb1 significantly downregulated BV-induced ER stress by inhibiting ROS generation and following the activation of Bip/eIF2α/CHOP signaling in HK2 cells. Subsequently, BV-triggered EMT and renal fibrosis were both ameliorated by ginsenoside Rb1. In summary, our findings suggested that BV-induced ROS promoted the appearance of EMT and renal fibrosis mainly via Bip/eIF2α/CHOP-mediated ER stress. This ER stress-related toxic pathway might be a potential intervention target for BV-caused renal fibrosis, and ginsenoside Rb1 would be a promising drug against BV- or Fructus Psoraleae-induced nephrotoxicity.

Combined use of Panax notoginseng and leech provides new insights into renal fibrosis: Restoration of mitochondrial kinetic imbalance

“…However, in the case of oral herbal remedies, therapeutic compounds are more likely to be found in the blood of patients and animals who have consumed them [31]. Previous research has also shown that Ginsenoside Rb1 and Salvianolic Acid D not only protect against renal fibrosis but are also linked to the restoration of mitochondrial function [32][33][34]. Additionally, Dimethylcurcumin and curcumenol have demonstrated efficacy in treating renal disorders [35,36].…”

Endoplasmic Reticulum Dysfunction: An Emerging Mechanism of Vitiligo Pathogenesis

“… 96 In other disease models, ginsenoside Rb1 inhibited ROS generation and overactivated ERS, and decreased cytoplasmic Ca2+ release to ameliorate renal fibrosis. 97 In addition, narrow‑band ultraviolet B phototherapy is effective in treating vitiligo. 98 The current study found that combined NB-UVB and adipose‑derived stem cell transplantation was beneficial to MBZ-induced vitiligo mice.…”

Renal function protection and the mechanism of ginsenosides: Current progress and future perspectives

“…In addition, the possible protective effects and mechanisms of ginsenoside Rb1 on oxidative damage and renal interstitial fibrosis in rats with unilateral ureteral obstruction (UUO) have been widely studied. Fan et al found that ginsenoside Rb1 significantly inhibited renal interstitial fibrosis in UUO rats by down-regulating TGF-β1 ( Xie et al 2009 ) expression or ihibiting Bip/eIF2α/CHOP signaling-mediated EMT ( Ni et al 2022 ). There are reports that ginsenoside Rb1 treats acute kidney injury by activating the Nrf2/ARE pathway which acts against oxidative stress ( Sun et al 2012 ).…”