Protective Effect of Rehmannioside A on Podocyte Injury in Rats with Chronic Kidney Disease by Regulating SIRT1/Nrf2/GPX4 Ferroptosis Pathway

Zhichun HUANG; Li JIANG; Luyao YOU; Jianhui CHEN; Cong ZHANG

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Zhichun HUANG, Li JIANG, Luyao YOU, Jianhui CHEN, Cong ZHANG. Protective Effect of Rehmannioside A on Podocyte Injury in Rats with Chronic Kidney Disease by Regulating SIRT1/Nrf2/GPX4 Ferroptosis Pathway[J]. Journal of Kunming Medical University.

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Protective Effect of Rehmannioside A on Podocyte Injury in Rats with Chronic Kidney Disease by Regulating SIRT1/Nrf2/GPX4 Ferroptosis Pathway

1.
Department of Geriatrics
2.
Department of Respiratory Medicine，Chengdu Longquanyi District Hospital of Traditional Chinese Medicine/Longquan Hospital Affiliated to Chengdu University of Traditional Chinese Medicine，Chengdu Sichuan 610101
3.
Emergency Department，Sichuan Hospital of Integrated Traditional Chinese and Western Medicine，Chengdu Sichuan 610000，China

Received Date: 2026-03-16
Available Online: 2026-10-29

Abstract

Abstract

Objective To investigate the protective effect and mechanism of rehmannioside A （ReA） on podocyte damage in rats with chronic kidney disease （CKD）. Methods Construct CKD rat model by administering adenine via gavage. The rats that were successfully modeled were randomly divided into the model group, a ReA-L group [administered 40.0 mg/(kg·d) of ReA by gavage], a ReA-H group [administered 80.0 mg/(kg·d) of ReA by gavage], and a ReA-H+Erastin group [administered 80.0 mg/(kg·d) of ReA by gavage and 10 mg/(kg·d) of the ferroptosis activator Erastin by intraperitoneal injection], with 12 rats in each group, continuous treatment for 4 weeks. An additional 12 healthy rats were selected as the control group. Collect 24-hour urine and abdominal aortic blood from rats for testing renal and liver function indicators. Observation of renal tissue pathological changes by hematoxylin-eosin (HE) and Masson staining. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detection of mRNA levels of podocyte marker in kidney tissue. Transmission electron microscopy observation of podocyte ultrastructure. Determined the content of oxidative stress and ferroptosis-related indicators in rat kidney tissues using the corresponding assay kits. Western blot detection of ferritin heavy chain 1 (FTH1), acyl-CoA synthetase long-chain family member 4 (ACSL4) proteins in kidney tissue, as well as the expression of proteins related to the silent information regulator 1 (SIRT1)/nuclear factor E2-related factor 2 (NRF2)/glutathione peroxidase 4 (GPX4) pathway. Results Compared with the control group, the glomerular basement membrane in the model group rats was thickened, a large amount of blue collagen deposition was observed, most foot processes were fused, some were hypertrophied, the glomerular basement membrane (GBM) was thickened, and the glomerulosclerosis score increased (P < 0.05), and 24-hour urine protein quantification (24 h UTP), blood urea nitrogen (BUN), serum creatinine (SCR) levels, desmin mRNA expression, malondialdehyde (MDA), 4-Hydroxy-2-nonenal (4-HNE), ferrous ion (Fe²⁺), prostaglandin-endoperoxide synthase 2 (PTGS2) content, and FTH1, ACSL4 protein expression were increased (P < 0.05), while The expression of Nephrin, Podocin, and Wilms' tumor protein 1 (WT1) mRNA, the content of glutathione (GSH) and superoxide dismutase (SOD), as well as the expression of SIRT1, p-NRF2, and GPX4 proteins were reduced (P < 0.05). Compared with the model group, the ReA-L group, ReA-H group, and ReA-H Erastin group showed a reduction in most fusion phenomena of podocytes, and the degree of GBM thickening, and the glomerulosclerosis score decreased (P < 0.05), and the levels of 24 h UTP, BUN, and SCR, desmin mRNA expression, MDA, 4-HNE, Fe²⁺, PTGS2 content, as well as FTH1 and ACSL4 protein expression were reduced (P < 0.05), while Nephrin, Podocin, WT1 mRNA expression, GSH and SOD content, as well as SIRT1, p-NRF2, and GPX4 protein expression were increased (P < 0.05). Compared with the ReA-H group, the ReA-H+Erastin group partially reversed the improvement effect of ReA-H on oxidative stress, ferroptosis, and podocyte injury in CKD rats (P < 0.05). There was no statistically significant difference in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels among the groups (P > 0.05). Conclusion ReA can inhibit oxidative stress and ferroptosis and alleviate podocyte damage in CKD rats, and its mechanism may be related to the activation of the SIRT1/NRF2/GPX4 pathway.
- Rehmannioside A,
- SIRT1/NRF2/GPX4 signaling axis,
- Ferroptosis,
- Chronic kidney disease,
- Podocytes

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References(35)

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