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Abstract: SA-PO343

TRIM72 Immunomodulatory Functions Protect the Kidney During Inflammation

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • Lin, Pei-Hui, The Ohio State University, Columbus, Ohio, United States
  • Duann, Pu, The Ohio State University, Columbus, Ohio, United States
  • Li, Haichang, The Ohio State University, Columbus, Ohio, United States
  • Rovin, Brad H., The Ohio State University, Columbus, Ohio, United States
Background

TRIM72 (MG53) is a muscle-predominant protein and functions as a circulating myokine that appears to confer tissue protection during ischemia-reperfusion (I/R) acute kidney injury and UUO-mediated kidney fibrosis. We discovered the functional duality of TRIM72 in kidney protection serving as a membrane repair protein and also modulating the immune system by suppressing NF-kB signaling during kidney inflammation. Here we explored the biological role and therapeutic potential of engineered MG53-containing extracellular vehicles (EVs) in the treatment of kidney inflammation.

Methods

TRIM72 protein expression was characterized in human kidney, immortalized kidney parenchymal cell lines, and mouse proximal tubular epithelial cells derived from wildtype (mg53 +/+) or trim72-null (mg53 -/-) age and gender-matched mice. We investigated whether I/R- injured kidney recruits circulating TRIM72-containing EVs as a means of protection. Furthermore, we engineered TRIM72 expression in several cell systems and further investigated whether TRIM72 affected the cells’ inflammatory cytokine profiles.

Results

TRIM72 expression was detected in total human kidney lysates and in immortalized human podocytes and mesangial cells. A serum pro-inflammatory cytokine panel confirmed elevation of pro-inflammatory cytokines in trim72-null mice. The relative fold increase in trim72-null mice compared to wildtype mice were: CXCL1--1.2; IL-2 --1.6; TNFa --1.38; IL-5 -- 2.8; IL-1--1.5. I/R-injured kidneys recruited TRIM72-containing EVs derived from C2C12 myotubes as shown by IVIS imaging of DiR-labeled EVs 2 hours post-injury. The kidneys from trim72 null mice that received C2C12 EVs over 4 weeks expressed comparable levels of TRIM72 to that of wildtype mice.

Conclusion

TRIM72 is detected in the kidney may be an endogenous inhibitor of pro-inflammatory cytokine expression. EVs loaded with TRIM72 are recruited to acutely injured kidneys, and can replenish renal TRIM72 levels in trim72 null mice. These results suggest that TRIM72-loaded EVs may be applied therapeutically to control kidney inflammation.

Funding

  • NIDDK Support