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26 April 2019 : Original article  

Mesenchymal Stem Cells Reverse Diabetic Nephropathy Disease via Lipoxin A4 by Targeting Transforming Growth Factor β (TGF-β)/smad Pathway and Pro-Inflammatory Cytokines

Yihua Bai1BE, Jiaping Wang2C, Zhenkun He1CF, Min Yang1CD, Luohua Li1E, Hongying Jiang1A*

DOI: 10.12659/MSM.914860

Med Sci Monit 2019; 25:3069-3076


BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesenchymal stem cells (MSCs) treatment has been proved to be effective in DN models by protecting renal function and preventing fibrosis. However, the underlying mechanism is unclear. Previous research indicated diabetes and associated complications may be attributed to failed resolution of inflammation, which is deliberately regulated by pro-resolving lipids, including lipoxins (LXs), resolvins (Rv) D and E series, protectins, and maresins. In this study, we monitored pro-resolving mediators in a DN model to explore the mechanism of MSCs treatment.

MATERIAL AND METHODS: The DN model was induced by STZ injection in SD rats. UPLC-MS/MS was performed to determine pro-resolving lipids in kidney tissue and serum of DN model before and after MSCs treatment, as well as in supernatants of HBZY-1-MSCs co-culture.

RESULTS: LXA4 was highly accumulated in renal tissue of DN rats with MSCs treatment; ex vivo, LXA4 was significantly increased in the supernatants of HBZY-1 cells co-cultured with MSCs in a high-glucose (HG) medium. Western blot analysis indicated that ALX/FPR2, the receptor of LXA4, was markedly expressed in renal tissue of the DN-MSC group and HBZY-1 after incubating with MSCs in HG. Intraperitoneal injection of LXA4 inhibited renal fibrosis by targeting TGF-β/Smad signaling and downregulated serum TNF-α, IL-6, IL-8, and IFN-γ in DN rats. Notably, all the protective effects induced by MSCs or LXA4 were abolished by ALX/FRP2 blocking.

CONCLUSIONS: Our results demonstrate that MSCs intervention prevented DN procession via the LXA4-ALX/FPR2 axis, which inhibited glomerulosclerosis and pro-inflammatory cytokines, eventually contributing to kidney homeostasis.

Keywords: Lipoxins, mesenchymal stromal cells, Receptors, Transforming Growth Factor beta, Cytokines, Diabetes Mellitus, Experimental, Docosahexaenoic Acids, Fibrosis, Inflammation Mediators, Mesenchymal Stem Cell Transplantation, Signal Transduction, Smad Proteins, Transforming Growth Factor beta


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Medical Science Monitor Basic Research eISSN: 2325-4416
Medical Science Monitor Basic Research eISSN: 2325-4416