Dietary secoisolariciresinol diglucoside alleviates chronic kidney disease in offspring rats caused by maternal trans-fatty acid exposure by regulating the Bcl-2/Bax/caspase-3 signaling axis

doi:10.12122/j.issn.1673-4254.2025.12.13

Abstract

Abstract:

Objective To investigate the potential mechanism underlying the protective effect of secoisolariciresinol diglucoside (SDG) against chronic kidney disease (CKD) in offspring mice caused by maternal exposure to trans fatty acids (TFA) during pregnancy and lactation. Methods Thirty female C57BL/6 mice were randomized into control group, TFA model group, and 3 TFA model groups treated with SDG at low, medium and high doses (10, 20 and 30 mg/kg, respectively). The changes in blood urea nitrogen (BUN) and serum creatinine (CRE) levels of the mice were measured. Network pharmacology analysis was conducted to explore protective mechanism of SDG against TFA-induced renal injury, and molecular docking was used to assess the binding affinity of SDG to Bcl-2, Bax, and caspase-3. The protein expressions of cleaved caspase-3, Bax, and Bcl-2 in the renal tissues of the offspring mice were detected with Western blotting. Result The mice in TFA group showed significantly higher BUN and CRE levels than those in the control group. Treatment with SDG at the medium and high doses significantly reduced BUN and CRE levels in the mouse models. Network pharmacology and molecular docking suggested that SDG ameliorated renal injury by targeting the apoptosis-related Bcl-2/Bax/caspase-3 axis. The results of Western blotting showed the mouse models in TFA exposure group had increased renal cell apoptosis with elevated expression levels of cleaved caspase-3 protein and a decreased Bcl-2/Bax ratio (P<0.05), and intervention with SDG at all the 3 doses significantly reduced renal cell apoptosis and renal expression of cleaved caspase-3 and increased the Bcl-2/Bax ratio in the mouse models. Conclusion Maternal TFA exposure during gestation and lactation induces renal injury in offspring mice. Dietary SDG intervention can mitigate TFA-induced renal injury in offspring mice possibly by suppressing renal cell apoptosis via regulating the Bcl-2/Bax/caspase-3 signaling axis.

Key words: secoisolariciresinol diglucoside, trans-fatty acid, chronic kidney disease, nutrition interventions, apoptosis, Bcl-2/Bax/caspase-3

Siyu MA, Meiqing CHEN, Tianyu WU, Wenhong ZHAO. Dietary secoisolariciresinol diglucoside alleviates chronic kidney disease in offspring rats caused by maternal trans-fatty acid exposure by regulating the Bcl-2/Bax/caspase-3 signaling axis[J]. Journal of Southern Medical University, 2025, 45(12): 2658-2666.

Figures/Tables 7

Tab.1 Comparison of blood urea nitrogen (BUN) and serum creatinine (CRE) levels among the 5 groups (Mean±SD, n=9)

Group	BUN (mmol/L)	CRE (μmol/L)
Control	17.08±1.53	44.85±6.087
TFA	22.39±6.18^#	68.54±11.89^#
TFA+LSDG	18.84±3.91	67.22±10.96
TFA+MSDG	15.56±1.86*	60.76±7.62
TFA+HSDG	17.01±3.57*	52.49±6.22
F	3.98	10.81
P	<0.01	<0.001

Fig.1 Network pharmacology analysis of the protective mechanism of SDG against TFA-induced chronic kidney disease (CKD). A: Collection of SDG targets. B: DO enrichment analysis of SDG targets. C: KEGG enrichment analysis of SDG targets. D: Screening of potential targets involved in the protective effects of SDG against TFA-induced CKD. E: KEGG enrichment analysis of the pathways mediating the protective effects of SDG against CKD.

Fig.2 Cell apoptosis in the kidney tissue of the offspring mice in each group. A: TUNEL staining of the kidney tissue (the white arrows indicate apoptotic cells). B: Statistical chart of cell apoptosis in kidney tissue of the offspring mice in each group. #P<0.05 vs control group; *P<0.05 vs TFA group.

Fig.3 Immunohistochemical staining for cleaved caspase-3 in the renal tissues of the offspring mice in each group (scale bar=50 μm). A: Control group. B: TFA group. C: TFA+LSDG group. D: TFA+MSDG group. E: TFA+HSDG group. F: Quantitative statistical chart. #P<0.05 vs Control group; *P<0.05 vs TFA group.

Fig.4 Screening of the key targets of SDG in the treatment of TFA-induced CKD (A) and molecular docking results of Bcl-2, Bax and caspase-3 with SDG (B-D).

Tab. 2 The PDB database code names for each protein

Target	PDB ID
Bcl-2	1g5m
Bax	4bd6
Caspase-3	1gfw

Fig.5 Detection of protein expressions of apoptosis-related proteins in kidney tissue of the offspring mice in each group. A: Protein bands of caspase-3, Bcl-2 and Bax in the kidney tissues of the offspring mice in each group detected with Western blotting. B: Gray value of caspase-3 in each group. C: Gray value ratio of Bcl2/Bax in each group. #P<0.05 vs control group; *P<0.05 vs TFA group.

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