ACE in Neutrophils Ameliorates Glomerular Damage in Immune Complex-Mediated Crescentic Glomerulonephritis via Complement C3 and C and N Domains of ACE

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Background: Angiotensin-converting enzyme (ACE) is composed of catalytically active C and N domains, and widely known to regulate blood pressure as a major component of the renin-angiotensin system. We recently reported that glomerular injury of immune-complex (IC) mediated crescentic glomerulonephritis (GN) was attenuated in the mice overexpressing ACE specifically in neutrophils (NeuACE mice). Mechanistically, the renoprotective role was mediated by complement C3b-complement receptors 1/2 (CR1/2): C3b-CR1/2 axis. NeuACE mice showed increased level of serum C3b. NeuACE neutrophils exhibited enhanced IC uptake with elevated surface expressions of CR1/2 and FcγRs. Here, we further investigate the precise mechanism of the neutrophilic ACE-mediated renoprotective effects in GN. Methods: Nephrotoxic serum nephritis (NTN) was induced in the mice with four different conditions, and analyzed in renal function and histology: 1) Neutrophils were depleted in WT and NeuACE mice by administering anti-neutrophil Ab. 2) ACE-overexpressed neutrophils were adoptively transferred into WT mice. 3) ACE C-domain KO (Tg-CKO) mice, ACE N-domain KO (Tg-NKO) mice, and WT-ACE transgenic (Tg-ACE) mice were also examined. 4) Lastly, NeuACE mice that lack complement C3 (NeuACE-C3KO) and C3KO mice were compared. Results: 1) WT mice without neutrophils showed amerioliated glomerular injury in proteinuria and histology, while NeuACE mice lacking neurophils lost the renoprotective effect. In WT mice, neutorphils are needed for glomerular injury; in NeuACE mice, neutrophils are required for the renoprotection. 2) WT mice with ACE-overexpressing neutrophils exhibited less severe glomerular injury. 3) Tg-CKO or Tg-NKO showed partially lost the renoprotective role compared with Tg-ACE mice, likely both C and N domains are needed for full renoprotection. 4) Furthermore, NeuACE-C3KO mice did not show the renoprotective effects of overexpressed ACE in neurophils anymore, compared with C3KO mice. Complement C3 is essential for the renoprotective role of overexpressed ACE in neutrophils in NeuACE mice. Conclusion: The renoprotective effects of overexpressed ACE in NeuACE mice in IC-mediated GN require specifically neutrophils, both C and N domains of ACE, and complement C3.

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