Objectives: TLR signaling plays important role in renal ischemia reperfusion injury (IRI). MyD88 is the key adapter molecule in TLR pathway. This study try to explore if inhibiting TLR signals by a self-created MyD88 inhibitor TJ-M2010-2 can provide protection against renal IRI. Methods: MR1 was used as CD154 blockade, TJ-M2010-2, a self-created molecule (patented), as MyD88 blockade. 84 male BALB/C mice were divided into 6 groups, 14 mice for each group (8 for survival observation): the IRI group, MR1 group, TJ-M2010-2 group, MyD88KO group and the TJ-M2010-2+MR1 group. Renal IRI was induced by clamping the left renal pedicle for 80min, and removing the right kidney immediately after the end of the clamping. Partial mice were sacrificed and kidneys were collected on 1d, 3d, and 7d for the detection of NF-kB expression, ROS production, MPO expression, and histological examination; serum were collected at 24h for detection of IL-1b, IL-6, TNF-a and IL-10. The therapeutic effects were evaluated in renal functions after 24h, 3d and 7d of reperfusion. TUNEL assays were used. Results: The mortality of TJ-M2010-2 group declined from 87.5% to 62.5%, while the TJ-M2010+MR1 group greatly decreased to 0% (Fig 1). Compared with saling contol, TJ-M2010-2, MR1 and TJ-M2010-2+MR1 groups exhibited lower BUN and Cr level (24.83±17.28, 154.8±8.044, 24.14±8.295 versus 167.4±19.81; P=0.0005, P=0.3386, P=0.0001). The activation of NF-kB was greatly inhibited, so were the downstream cytokines IL-1b, IL-6, TNF-a, ICAM-1, however, the IL-10 level was increased remarkably. The histological and immunopathologic score of renal tissues show an alleviative injury in TJ-M2010+MR1 group. Conclusion: Co-blocking TLR/MYD88 and CD154-CD40 pathways simultaneously showed much stronger protective effect, suggesting a very robust protection effect against renal IRI can be observed when blocking both innate and acquired immune systems at the same time. TJ-M2010-2 has a very promising clinical potential as a MyD88 inhibitor.

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