Poly(I:C)-Induced Mesenchymal Stem Cells Protect the Kidney Against Ischemia/Reperfusion Injury via the TLR3/PI3K Pathway
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Updated: Oct 10, 2025
Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
Tian Chen1,2, Yamei Jiang1,2, Shihao Xu1,2
1Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Objective: To investigate the effect and protective mechanism of mesenchymal stem cell subpopulations on acute kidney injury by establishing a mouse model of renal ischemia-reperfusion injury. Methods: Male C57BL/6 mice were randomly divided into five groups, namely, sham-operation group and those treated with normal saline, untreated mesenchymal stem cells, mesenchymal stem cells treated with lipopolysaccharide (LPS, pro-inflammatory phenotype) and mesenchymal stem cells treated with polyinosinic-polycytidylic acid (poly[I:C], anti-inflammatory phenotype) respectively. The renal function, histopathological damage, circulating inflammation levels and antioxidant capacity of mice were evaluated. The PI3 kinase p85 (PI3K) inhibitor was added into the conventional mesenchymal stem cell cultures in vitro to observe its effects on the secretion of anti-inflammatory cytokines. Results: Mesenchymal stem cells treated with poly(I:C) (anti-inflammatory phenotype) could effectively reduce serum creatinine and blood urea nitrogen, attenuate histopathological damage and apoptosis level, decrease the level of circulating pro-inflammatory cytokines and increase the level of circulating anti-inflammatory cytokines, enhance peroxidase activity and reduce malondialdehyde content at each time point. After the addition of the PI3K inhibitor, the mRNA expression and protein secretion of indoleamine 2,3-dioxygenase 1 and heme oxygenase 1 of various mesenchymal stem cells were significantly reduced, and that of mesenchymal stem cells treated with poly(I:C) (anti-inflammatory phenotype) was more obvious. Conclusions: Polyriboinosinic-polyribocytidylic acid (poly[I:C]), a synthetic double-stranded RNA, whose pretreatment induces mesenchymal stem cells to differentiate into the anti-inflammatory phenotype. Anti-inflammatory mesenchymal stem cells induced by poly(I:C) can better protect renal function, alleviate tissue damage, reduce circulating inflammation levels and enhance antioxidant capacity, and achieve stronger anti-inflammatory effects through the TLR3/PI3K pathway.
Insights
Pretreating mesenchymal stem cells with poly(I:C) induces an anti-inflammatory phenotype, significantly protecting against acute kidney injury by reducing inflammation and enhancing antioxidant capacity via the TLR3/PI3K pathway.
Area of Science:
- Nephrology
- Immunology
- Stem Cell Biology
Background:
- Acute kidney injury (AKI) following renal ischemia-reperfusion injury (IRI) presents a significant clinical challenge.
- Mesenchymal stem cells (MSCs) show therapeutic potential, but their protective mechanisms and optimal phenotypes require further elucidation.
- Understanding the role of specific signaling pathways, like TLR3/PI3K, is crucial for harnessing MSC immunomodulatory capabilities.
Purpose of the Study:
- To investigate the protective effects and underlying mechanisms of distinct mesenchymal stem cell (MSC) subpopulations on acute kidney injury (AKI) in a mouse model.
- To evaluate the impact of inducing an anti-inflammatory phenotype in MSCs using polyinosinic-polycytidylic acid (poly[I:C]) on renal function and inflammation.
- To explore the involvement of the PI3 kinase (PI3K) pathway in mediating the anti-inflammatory and protective effects of MSCs.
Main Methods:
- Establishment of a mouse model of renal ischemia-reperfusion injury (IRI).
- Treatment groups included sham operation, normal saline, untreated MSCs, LPS-treated (pro-inflammatory) MSCs, and poly[I:C]-treated (anti-inflammatory) MSCs.
- Assessment of renal function (serum creatinine, BUN), histopathology, circulating cytokines, antioxidant capacity, and the effect of PI3K inhibition on MSCs in vitro.
Main Results:
- Poly[I:C]-treated MSCs (anti-inflammatory phenotype) significantly improved renal function, reduced kidney damage and apoptosis, decreased pro-inflammatory cytokines, and increased anti-inflammatory cytokines.
- This group also demonstrated enhanced peroxidase activity and reduced malondialdehyde levels, indicating improved antioxidant capacity.
- Inhibition of PI3K significantly reduced the expression and secretion of key enzymes (IDO1, HO-1) involved in MSC immunomodulation, particularly in poly[I:C]-treated MSCs.
Conclusions:
- Polyriboinosinic-polyribocytidylic acid (poly[I:C]) effectively induces MSCs to adopt an anti-inflammatory phenotype.
- Anti-inflammatory MSCs generated by poly[I:C] pretreatment offer superior protection against renal IRI, improving function and reducing tissue damage.
- The protective effects are mediated, at least in part, through the Toll-like receptor 3 (TLR3)/PI3K pathway, highlighting a novel therapeutic strategy for AKI.
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