ACE in Granulocytes Has a Protective Role in Crescentic Glomerulonephritis via Complement Lectin Pathway Independent of Angiotensin II
- Glomerular Diseases: From Inflammation to Fibrosis - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
- Saito, Suguru, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Tatsumoto, Narihito, Cedars-Sinai Medical Center, Los Angeles, California, United States
- Yamashita, Michifumi, Cedars-Sinai Medical Center, Los Angeles, California, United States
ACE is a well-known enzyme to regulate blood pressure and inflammation, and structurally having two enzymatic domains: N-domain and C-domain. Its C-domain regulates blood pressure by producing angiotensin II in renin-angiotensin system. We recently reported a novel function of ACE: ACE overexpressed neutrophils have a protective role in immune complex (IC)-mediated crescentic glomerulonephritis (GN) via complement C3b-CR1/2 axis, efficiently removing IC deposits. Here, we show that ACE C-terminal catalytic domain is responsible for the renoprotective role in myeloid cells in crescentic GN via lectin pathway.
We induced the nephrotoxic serum nephritis (NTN) in C57Bl/6 (WT), Jwt mice that overexpressing ACE in myeloid cells (neutrophils and monocytes/macrophages), Jcko mice that overexpressing C-domain knockout ACE in myeloid cells, and Jnko mice that overexpressing N-domain knockout ACE in myeloid cells, and evaluated renal function and histology (crescent formation and fibrinoid necrosis). In addition, we examined complement pathway activation in vitro and blood angiotensin II level.
7 days after induction of NTN, Jwt mice showed less severe proteinuria and mild histological glomerular damages, showing overexpressed ACE in neutrophils and monocytes/macrophages has the protective role in IC-mediated crescentic GN. When we induced NTN in Jcko mice and Jnko mice, Jcko mice lost the renoprotective effects and Jnko mice still showed the severe glomerular damage. These data clearly showed that ACE C-domain, but not N-domain, has the renoprotective role. Regarding complement activation, recombinant ACE activated lectin pathway, but not classical and alternative pathways. Given the normal blood pressure level and the normal plasma angiotensin II level in all these mouse strains, the ACE C-domain mediated renoprotective effect is independent of angiotensin II.
ACE C-domain in granulocytes has a protective role in crescentic glomerulonephritis via complement lectin pathway independent of Angiotensin II.
Dual effects of ACE C-domain in kidney disease