Qigui didang decoction alleviates renal injury in a diabetic kidney disease model with metabolic memory features: association with ferroptosis and the SIRT1/Nrf2 pathway

TL;DR

This study shows that Qigui didang decoction helps reduce kidney damage in diabetic rats by targeting ferroptosis and the SIRT1/Nrf2 pathway.

Contribution

The study reveals a novel mechanism of QGDD in mitigating diabetic kidney disease through the SIRT1/Nrf2 pathway and ferroptosis regulation.

Findings

QGDD reduced kidney injury markers and oxidative stress in diabetic rats.

Medium-dose QGDD showed optimal effects by activating the SIRT1/Nrf2 pathway and inhibiting ferroptosis.

QGDD mitigated metabolic memory by lowering AGEs accumulation.

Abstract

This study aims to evaluate the renoprotective effects of QGDD in a DKD model exhibiting metabolic memory features and to explore its potential mechanism involving the regulation of ferroptosis via the SIRT1/Nrf2 signaling pathway.

A DKD rat model was induced using streptozotocin (STZ). The rats were assigned to the Blank Control Group (C), Model Group (M), Metformin group (Met), and low-, medium-, and high-dose QGDD groups (QGDD-L/M/H). Intervention effects were assessed by monitoring body weight, fasting blood glucose, renal function markers (24-UTP, BUN, Scr, Cys-C, β2-MG), renal histopathology (HE/Masson staining), oxidative stress markers (Fe2+, MDA, GSH, SOD), cell death indicators (TUNEL, ROS), and expression of genes and proteins associated with the SIRT1/Nrf2 pathway (RT-qPCR, Western blot).

All QGDD dose groups decreased 24-hour urinary protein excretion and serum levels of BUN, Scr, Cys-C, and β2-MG. The medium-dose QGDD group notably reduced renal Fe2+ and MDA levels, increased GSH and SOD activity, and inhibited ROS accumulation and cellular apoptosis. QGDD activated the SIRT1/Nrf2 pathway, significantly upregulating the mRNA and protein expression of Nrf2, HO-1, and GPX4, while suppressing the accumulation of AGEs and Ferritin.

QGDD mitigated the persistent elevation of AGEs, a hallmark of metabolic memory in DKD by activating the SIRT1/Nrf2 signaling pathway to inhibit ferroptosis-associated lipid peroxidation and oxidative stress. Its multi-target synergistic effects provide a solid experimental foundation for the use of Chinese herbal formulations in treating DKD. The medium-dose group demonstrated optimal therapeutic efficacy, emphasizing the significance of dose optimization.

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