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

Abstract

Acute kidney injury (AKI) represents a prevailing complication of sepsis, and its onset involves ferroptosis. Ginsenoside Rg1 exerts a positive effect on kidney diseases. This study explored the action of ginsenoside Rg1 in sepsis‐induced AKI (SI‐AKI) by regulating ferroptosis in renal tubular epithelial cells (TECs). Sepsis rat models were established using cecal ligation and puncture (CLP) and cell models were established by treating human renal TECs (HK‐2) with LPS to induce ferroptosis. Serum creatinine (SCr) and blood urea nitrogen (BUN) and urine KIM1 contents in rats were determined by ELISA kits. Kidney tissues were subjected to immunohistochemical and H&E stainings. Iron concentration, malondialdehyde (MDA), glutathione (GSH), and ferroptosis‐related protein (ferritin light chain [FTL], ferritin heavy chain [FTH], GSH peroxidase 4 [GPX4], and Ferroptosis suppressor protein 1 [FSP1]) levels in kidney tissues and HK‐2 cells were measured using ELISA kits and Western blotting. HK‐2 cell viability was detected by cell counting kit‐8, and cell death was observed via propidium iodide staining. Reactive oxygen species accumulation in cells was detected using C11 BODIPY 581/591 as a molecular probe. In CLP rats, ginsenoside Rg1 reduced SCr, BUN, KIM1, and NGAL levels, thus palliating SI‐AKI. Additionally, ginsenoside Rg1 decreased iron content, FTL, FTH, and MDA levels, and elevated GPX4, FSP1, and GSH levels, thereby inhibiting lipid peroxidation and ferroptosis. Moreover, FSP1 knockdown annulled the inhibition of ginsenoside Rg1 on ferroptosis. In vitro experiments, ginsenoside Rg1 raised HK‐2 cell viability and lowered iron accumulation and lipid peroxidation during ferroptosis, and its antiferroptosis activity was dependent on FSP1. Ginsenoside Rg1 alleviates SI‐AKI, possibly resulting from inhibition of ferroptosis in renal TECs through FSP1.

Preparation, structural characterization, antioxidant activity and protection against cisplatin-induced acute kidney injury by polysaccharides from the lateral root of Aconitum carmichaelii

“…Previous studies have shown that resveratrol protects against cisplatin-induced acute kidney injury by improving MDA, GSH, and endogenous antioxidant enzyme activity and improving the in vivo metabolism of cisplatin ( Darwish et al, 2018 ; Ibrahim et al, 2018 ). Guo et al found that ginsenoside Rg1 inhibited ferroptosis by reducing iron accumulation and inhibiting lipid peroxidation ( Guo et al, 2022 ). In the present study, we demonstrated that RFP could effectively reduce lipid peroxidation production while increasing the level of the antioxidant enzyme GSH in a cisplatin-induced mouse model of acute kidney injury, suggesting that RFP could alleviate cisplatin-induced oxidative damage induced by acute kidney injury.…”

CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress

“…3,4 It has been demonstrated that the pathogenesis of sepsis-induced AKI is closely associated with inflammatory response, apoptosis, oxidative stress, and ferroptosis. [6][7][8] CHAC1 is identified as a mammalian pro-apoptotic factor, 13 which may be involved in apoptosis, oxidative stress, and ferroptosis. In the present study, the level of CHAC1 was found to be up-regulated in the kidney tissues of mice with sepsisinduced MODS according to bioinformatic analysis.…”

“…35 In addition, the study conducted by Guo et al revealed that ginsenoside Rg1, belonging to the class of steroid glycosides, suppressed ferroptosis to improve sepsis-induced AKI. 6 Moreover, ferroptosis was involved in LPS-induced AKI through mitochondria-derived ROS. 36 In this study, our results also demonstrated that LPS treatment enhanced cell apoptosis, oxidative stress, and ferroptosis in HK-2 cells that were notably attenuated by the knockdown of CHAC1.…”

“…5 The development and progression of sepsis-induced AKI is an intricate crosstalk of multiple mechanisms, such as inflammatory response, oxidative stress, apoptosis, and ferroptosis. [6][7][8][9] Thus, despite advances in treatments, such as renal replacement, blood purification, and pharmacologic therapy, 10,11 high mortality and downthe-line outcomes still continue. 12 Therefore, exploring the potential molecular mechanisms of sepsis-induced AKI and seeking underlying targets could contribute to the development and improvement of therapies for sepsis-induced AKI.…”

Ferroptosis: A new insight for treatment of acute kidney injury

“…Another small molecule, ginsenoside Rg1, can improve the viability of HK-2 cells and reduce the accumulation of iron and lipid peroxidation. Its anti-ferroptosis activity is dependent on FSP1 ( Guo et al, 2022 ).…”