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. 2021 Aug 11;12(1):450.
doi: 10.1186/s13287-021-02447-x.

Human umbilical cord mesenchymal stem cells reduce oxidative damage and apoptosis in diabetic nephropathy by activating Nrf2

Ping Nie  1 , Xue Bai  1 , Yan Lou  1 , Yuexin Zhu  1 , Shan Jiang  1 , Lina Zhang  2 , Na Tian  2 , Ping Luo  3 , Bing Li  4
Affiliations

Human umbilical cord mesenchymal stem cells reduce oxidative damage and apoptosis in diabetic nephropathy by activating Nrf2

Ping Nie et al. Stem Cell Res Ther. .

Abstract

Background: Mesenchymal stem cells (MSCs) have a therapeutic effect on diabetic nephropathy (DN) but the underlying mechanism remains unclear. This study was conducted to investigate whether human umbilical cord-MSCs (hUCMSCs) can induce oxidative damage and apoptosis by activating Nrf2.

Methods: We used a type 2 diabetic rat model and a high-glucose and fat-stimulated human glomerular mesangial cell (hGMC) model. Western blotting, RT-qPCR, and TUNEL staining were performed on animal tissues and cultured cells. Nuclear expression of Nrf2 was detected in the renal tissue. Furthermore, Nrf2 siRNA was used to examine the effects of hUCMSCs on hGMCs. Finally, the effect of hUCMSCs on the Nrf2 upstream signalling pathway was investigated.

Results: After treatment with hUCMSCs, Nrf2 showed increased expression and nuclear translocation. After Nrf2-specific knockout in hGMCs, the protective effect of hUCMSCs on apoptosis induced by high-glucose and fat conditions was reduced. Activation of the PI3K signalling pathway may be helpful for ameliorating DN using hUCMSCs.

Conclusions: hUCMSCs attenuated renal oxidative damage and apoptosis in type 2 diabetes mellitus and Nrf2 activation is one of the important mechanisms of this effect. hUCMSCs show potential as drug targets for DN.

Keywords: Apoptosis; Diabetic nephropathy; Mesenchymal stem cell; Nrf2; Oxidative damage.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Timeline of animal experiment. Ctrl, control rats; MSC, control rats injected with hUCMSCs; DM, diabetic rats; DM/MSC, diabetic rats injected with hUCMSCs; T2DM, type 2 diabetes mellitus
Fig. 2
Fig. 2
Renoprotective role of human umbilical cord mesenchymal stem cells (hUCMSCs) assessed using general parameters and pathological changes. a Body weight. b Right kidney hypertrophy index. c Blood glucose. d Urinary albumin/creatinine ratio. e Serum creatinine. f Serum cholesterol. g Representative images of periodic acid–Schiff staining of kidney tissues from different groups (scale bar = 50 μm) and electron microscopy (scale bar = 3 μm). h Glomerular area in different groups. i Glomerular basement membrane width. n = 5–7 per group. *P < 0.05 vs. Ctrl group; #P < 0.05 vs DM group
Fig. 3
Fig. 3
Human umbilical cord mesenchymal stem cells (hUCMSCs) inhibit diabetes-induced oxidative stress and renal cell apoptosis. a Level of MDA as a marker of oxidative stress. b–d Protein level of 4-HNE as a marker of oxidative stress and those of caspase 3, Bcl-2 and Bax as markers of renal apoptosis evaluated via western blotting. e TUNEL assay was performed to evaluate apoptosis in renal tissue (green, scale bar = 50 μm). n = 5–7 per group. *P < 0.05 vs. Ctrl group; #P < 0.05 vs DM group. The effects of hUCMSCs on hGMCs were evaluated by measuring the GPX level in the supernatant of cell culture medium (f), protein level of 4-HNE (g), and CAT (h). control, control group; C/MSC, control and hUCMSC group; HG/P, high-glucose and palmitate group; HG/P/MSC, high-glucose, palmitate, and hUCMSC group. n = 6 per group. *P < 0.05, vs. control group; #P < 0.05, vs. HG/P group
Fig. 4
Fig. 4
Human umbilical cord mesenchymal stem cells (hUCMSCs) upregulated renal Nrf2 and downstream cytokine expression. a Immunohistochemical staining of Nrf2 (× 600). Effects of hUCMSCs on diabetic rats were compared at the protein level for total Nrf2 (b), HO-1 (g), NQO1 (f), and SOD2 (e) and at the RNA level for Nrf2 (c) and HO-1 (d). n = 5 per group. *P < 0.05 vs. Ctrl group; #P < 0.05 vs DM group. The effects of hUCMSCs on hGMCs were evaluated by measuring the protein levels of total Nrf2 (h), SOD2 (i), and HO-1 (j). control, control group; C/MSC, control and hUCMSC group; HG/P, high-glucose and palmitate group; HG/P/MSC, high-glucose, palmitate, and hUCMSC group. n = 6 per group. *P < 0.05, vs. control group; #P < 0.05, vs. HG/P group
Fig. 5
Fig. 5
Human umbilical cord mesenchymal stem cells (hUCMSCs) upregulated renal Nrf2 expression. The effects of hUCMSCs on diabetic rats were compared at the protein level for nuclear Nrf2 (a) and cytoplasmic Nrf2 (b). n = 5 per group. c Immunofluorescence staining for Nrf2 was performed (scale bar = 40 μm). *P < 0.05 vs. Ctrl group; #P < 0.05 vs DM group
Fig. 6
Fig. 6
Effect of Nrf2 on oxidative stress and apoptosis in human glomerular mesangial cells (hGMCs) in response to HG/P and human umbilical cord mesenchymal stem cell (hUCMSC) treatment determined by Nrf2 siRNA transfection. Protein expression of a Nrf2, b Bax, and c 4-HNE in hGMCs was measured via western blotting. control, control group; C/MSC, control and hUCMSC group; HG/P, high-glucose and palmitate group; HG/P/MSC, high-glucose, palmitate, and hUCMSC group; s-control, control group with Nrf2 siRNA; s-C/MSC, control and hUCMSC group with Nrf2 siRNA; s-HG/P, high-glucose and palmitate group with Nrf2 siRNA; s-HG/P/MSC, high-glucose, palmitate, and hUCMSC group with Nrf2 siRNA. n = 6 per group. *P < 0.05, vs. control group; #P < 0.05, vs HG/P group; &P < 0.05, vs. Nrf2 siRNA control group
Fig. 7
Fig. 7
Human umbilical cord mesenchymal stem cells (hUCMSCs) induce activation of the PI3K/Akt signalling pathway in human glomerular mesangial cells (hGMCs). Representative western blots of p-Akt, total Akt (a), p-PI3K, and total PI3K (b). n = 6 per group. *P < 0.05, vs. control group; #P < 0.05, vs HG/P group
Fig. 8
Fig. 8
Possible mechanisms for preventing diabetic nephropathy using human umbilical cord mesenchymal stem cells (hUCMSCs)
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