MG53 in Sepsis-Induced AKI: Underlying Mechanisms for Renoprotection

Background: MG53 (TRIM72) is a muscle-predominant protein and functions as a circulating myokine that appears to confer tissue protection. We previously showed that MG53 confers kidney protection in the face of ischemia-reperfusion (I/R) kidney injury and unilateral ureteral obstruction (UUO)-mediated kidney fibrosis. Compared to wild type littermates, kidneys of mg53-/- mice have increased F4/80+ and CD11b+ myeloid cell infiltration (from 4 - 5 months age) and develop age-dependent kidney fibrosis. Infiltration of these myeloid cells or sustained activation of kidney resident immune cells may contribute to this exacerbated fibrosis and/or impact recovery from acute kidney injury. In the present study, we explored the potential involvement of MG53 in sepsis-induced AKI (SI-AKI), a model with severe renal dysfunction and high mortality rate. Methods: We generated the mouse strain TRE-STOPflox-tPA-MG53 (ctPA-MG53) for conditional MG53 over-expression. This mouse strain was bred to LysMcre (myeloid expression) to induce doxycycline (DOX)-dependent conditional myeloid MG53-overexpression. We utilized a cecal ligation and perforation (CLP) animal model as SI-AKI to study the in vivo physiological role of elevated MG53 in myeloid cells on renoprotection and immune cell-kidney crosstalk associated with SI-AKI. We also isolated bone marrow derived macrophage (BMDM) for in vitro functional verification. Results: We confirmed the elevated serum and excessive myeloid-specific MG53 expression from our conditional myeloid-specific transgenic mice. Transgenic LysMcre; ctPAMG53 mice exhibited reduced F4/80+ macrophage infiltration compared to control mice and had improved kidney function (BUN assay) and reduced kidney injury (NGAL, Kim1) after SI-AKI. We also observed the expression level of MG53 changed from transgenic mice upon BMDM In vitro M1 and M2 polarization assay. Conclusion: We have established an in vivo animal system to study the impact of myeloid and circulating MG53 in SI-AKI. Elevated MG53 conferred renoprotection with functional improvement and reduced kidney injury. We also established an in vitro system to investigate the influence of MG53 on BMDM polarization. Funding: Other NIH Support - R01-AG062896, R21-AI166273