Placenta-derived mesenchymal stem cells protect against diabetic kidney disease by upregulating autophagy-mediated SIRT1/FOXO1 pathway

Abstract

Diabetic kidney disease (DKD) is a common chronic microvascular complication of diabetes mellitus. Although studies have indicated the therapeutic potential of mesenchymal stem cells (MSCs) for DKD, the underlying molecular mechanisms remain unclear. Herein, we explored the renoprotective effect of placenta-derived MSCs (P-MSCs) and the potential mechanism of SIRT1/FOXO1 pathway-mediated autophagy in DKD. The urine microalbumin/creatinine ratio was determined using ELISA, and renal pathological changes were detected by special staining techniques. Immunofluorescence was used for detecting the renal tissue expression of podocin and nephrin; immunohistochemistry for the renal expression of autophagy-related proteins (LC3, Beclin-1, SIRT1, and FOXO1); and western blotting and PCR for the expression of podocyte autophagy- and pathway-related indicators. We found that P-MSCs ameliorated renal tubular injury and glomerular mesangial matrix deposition and alleviated podocyte damage in DKD rats. PMSCs enhanced autophagy levels and increased SIRT1 and FOXO1 expression in DKD rat renal tissue, whereas the autophagy inhibitor 3-methyladenine significantly attenuated the renoprotective effect of P-MSCs. P-MSCs improved HG-induced Mouse podocyte clone5(MPC5)injury, increased podocyte autophagy, and upregulated SIRT1 and FOXO1 expression. Moreover, downregulation of SIRT1 expression blocked the P-MSC-mediated enhancement of podocyte autophagy and improvement of podocyte injury. Thus, P-MSCs can significantly improve renal damage and reduce podocyte injury in DKD rats by modulating the SIRT1/FOXO1 pathway and enhancing podocyte autophagy.

Keywords:

• Placenta-derived mesenchymal stem cells
• autophagy
• diabetic kidney disease
• SIRT1/FOXO1 pathway
• podocyte injury

Acknowledgements

The authors would like to thank the Stem Cell Engineering Research Center of Jiangxi Province for providing human placenta-derived mesenchymal stem cells.

Ethical approval and consent to participate

Our study protocol has been approved by the Research Committee of the First Affiliated Hospital of Nanchang University (Approval number: 2020-04). All procedures in this study were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. There are no human subjects in this article and informed consent is not applicable.

Authors’ contributions

Design: Jixiong Xu

Conduct/data collection: Jiao Wang and Honghong Liu.

Analysis: Jiao Wang, Honghong Liu, and Guanru Yue.

Writing manuscript: Jiao Wang and Honghong Liu.

Consent for publication

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by grants from the Jiangxi Provincial Key R&D Plan (no. 20201BBG71006), the National Natural Science Funds of China (no. 8216030486), the Natural Science Foundation of Jiangxi Province (no. 20224BAB216009), and the Science and Technology Plan of Jiangxi Health Planning Committee (no. SKJP220217702).