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Abstract: SA-PO800

Partial Rescue of Complement-Induced Organ Injuries in a Factor H Mutant Mouse by MASP3 Deficiency

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Kim, Hangsoo, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gullipalli, Damodara, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Miwa, Takashi, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sato, Sayaka, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Golla, Madhu, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Palmer, Matthew, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Song, Wen-Chao, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Complement is activated through three canonical pathways: classical pathway (CP), lectin pathway (LP) and alternative pathway (AP). MASPs was known as a component of LP, but according to recent reports, MASPs was also participate AP. MASP1 gene knock-out mice (MASP-1/3 lacked) showed no AP activity and furthermore, MASP3 was clarified that it was responsible for the AP activation through maturation of pro factor D. These findings open the door to developing MASP3 targeting therapy for AP mediated disease, but we need to confirm blocking MASP3 is truly effective in vivo. In this study, we tested whether MASP3 deficiency abrogate phenotypes of a murine atypical HUS(aHUS) model with complement factor H point mutation.

Methods

We generated MASP3 knockout mice (MASP3-/-) and crossed with complement factor H mutant mice(FHR/R) which showed thrombotic microangiopathy and systemic thrombophilia as we previously reported. We then compared FHR/R MASP3-/- with littermates, FHR/R MASP3 wild type(FHR/R) in survival, hemoglobin or platelet level, and histologic change in major organs including kidney.

Results

We found that MASP3 deficiency rescued FHR/R from thrombocytopenia, anemia and renal failure. They were also prevented from large vein thrombi in liver and kidney. However, about 30% of FHR/R MASP3-/- died of extra-renal organ injuries such as intestinal injury, pulmonary hemorrhage and cerebral ischemia.
We measured LPS based AP activity with 20% serum from mice and found that a complement AP activity in FHR/R MASP3-/- was significantly lower than that in FHR/R , but higher compared with that in FHR/R FD-/-.

Conclusion

These findings demonstrated that MASP3 could be therapeutic target for complement AP mediated diseases, but it is important to assess wheteher residual AP activity by pro-FD cause tissue injury in each setting.

Funding

  • Other NIH Support