Adverse functions of neutrophils are regulated by neutrophilic angiotensin-converting enzyme in immune complex-mediated crescentic glomerulonephritis

Neutrophils play a pathogenic role in immune complex (IC)-mediated crescentic glomerulonephritis (GN). Angiotensin-converting enzyme (ACE) plays a crucial role in regulating blood pressure and inflammation via angiotensin II. We recently reported that ACE-overexpressing neutrophils have the renoprotective role in IC-mediated crescentic GN by the complement C3b-complement receptor1/2 axis. Here, we further investigate the precise mechanism of the adverse, pathogenic, and renoprotective functions of neutrophils in GN. Nephrotoxic serum nephritis (NTN) was induced in the mice with four different conditions and analyzed: <i>1</i>) neutrophil depletion in wild-type (WT) and NeuACE mice that overexpress ACE specifically in neutrophils; <i>2</i>) adoptive transfer of ACE-overexpressing neutrophils into WT mice; <i>3</i>) analysis of ACE's catalytic C and N domains using each domain-knockout (Tg-CKO and Tg-NKO) and WT-ACE transgenic (Tg-ACE) mice; and <i>4</i>) comparison between C3KO and C3KO-NeuACE mice that overexpress ACE in neutrophils but lack of complement C3. The results were as follows: <i>1</i>) WT mice without neutrophils showed ameliorated glomerular injury, whereas neutrophil-depleted NeuACE mice lost the renoprotective effect; <i>2</i>) WT mice with ACE-overexpressing neutrophils exhibited less severe glomerular injury; <i>3</i>) Tg-CKO or Tg-NKO mice showed a partial loss of the renoprotective effects compared with Tg-ACE mice, suggesting both C and N domains are needed for full renoprotection; and <i>4</i>) C3KO-NeuACE mice lost the renoprotective effects. Complement C3 is essential for the renoprotection of overexpressed neutrophilic ACE in NeuACE mice. The present study demonstrated that canonical pathogenic effects of neutrophils were overcome by the noncanonical renoprotection by neutrophils through both C and N domains of ACE and complement C3.<b>NEW & NOTEWORTHY</b> We recently reported that NeuACE mice that overexpress angiotensin-converting enzyme (ACE), specifically in neutrophils, alleviate glomerular injury in immune complex-mediated crescentic glomerulonephritis by the complement C3b-complement receptor 1/2 axis. Here, we showed that catalytically active C and N domains of ACE were needed for full renoprotection, and complement C3 was essential for the renoprotective role of overexpressed neutrophilic ACE. Furthermore, we highlighted the neutrophils' canonical pathogenic and noncanonical renoprotective functions via neutrophilic ACE through complement C3 in glomerulonephritis.