Kidney Week

Abstract: SA-PO800

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

Session Information

• Genetic Diseases: Glomerulopathies - II
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

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

Hangsoo Kim,

• Gullipalli, Damodara, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Damodara Gullipalli,

• Miwa, Takashi, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Takashi Miwa,

• Sato, Sayaka, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Sayaka Sato,

• Golla, Madhu, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Madhu Golla,

• Palmer, Matthew, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew Palmer,

• Song, Wen-Chao, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Wen-Chao Song,

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(FH^R/R) which showed thrombotic microangiopathy and systemic thrombophilia as we previously reported. We then compared FH^R/R MASP3^-/- with littermates, FH^R/R MASP3 wild type(FH^R/R) in survival, hemoglobin or platelet level, and histologic change in major organs including kidney.

Results

We found that MASP3 deficiency rescued FH^R/R from thrombocytopenia, anemia and renal failure. They were also prevented from large vein thrombi in liver and kidney. However, about 30% of FH^R/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 FH^R/R MASP3^-/- was significantly lower than that in FH^R/R , but higher compared with that in FH^R/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