*Purpose: We previously showed that CD137 ligand (CD137L) reverse signaling play a central role in kidney ischemia-reperfusion injury (IRI) by amplifying acute renal injury. In this study, we explored whether CD137L signaling is involved in the tissue repair process during kidney IRI.

*Methods: Kidney ischemia-reperfusion injury was induced in C57BL/6 mice and 50 ug of CD137-Fc fusion protein per mouse was injected at day 1 after kidney IRI. The extent of renal injury, renal inflammation and tissue repair was analyzed using qRT-PCR and flow cytometry. Bone marrow-derived macrophages were stimulated with a copmbination of CD137-Fc abd GM-CSF and whole RNA sequencing was performed 24 hours after stimulation.

*Results: Firstly, injection of CD137-Fc fusion protein at day 1 after kidney IRI decreased renal inflammation and injury. These phenomena were associated with recruitment of a lower number of neutrophils and increase in the ratio of M2 macrophage-to-M1 macrophage. Secondly, administration of CD137-Fc enhanced expression of tissue repair genes, PDGFα, IL-22, Amphiregulin, IGF1, and TGF-β. Thirdly, there was a higher proliferation of tubular epithelial cells in CD137-Fc-injected mouse kidneys, concomitantly with increased expression of Vementin. Finally, ten days after kidney IRI, renal inflammation was almost completely resolved and renal macrophages showed a normal phenotype in CD137-Fc-injected mice. RNA seq data showed that CD137L signaling induced functionally different macrophages from naïve macrophages and GM-CSF and CD137L signaling synergistically increased expression of some anti-inflammatory and tissue-repair genes.

*Conclusions: In sum, our results indicate that CD137L signaling is indispensable for tissue repair following kidney IRI. Therefore, our findings have important clinical implications in kidney regeneration.

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