Overexpressed angiotensin-converting enzyme in neutrophils suppresses glomerular damage in crescentic glomerulonephritis

While angiotensin-converting enzyme (ACE) regulates blood pressure by producing angiotensin II as part of the renin-angiotensin sys-tem, we recently reported that elevated ACE in neutrophils promotes an effective immune response and increases resistance to infec-tion. Here, we investigate if such neutrophils protect against renal injury in immune complex (IC)-mediated crescentic glomerulonephritis (GN) through complement. Nephrotoxic serum nephritis (NTN) was induced in wild-type and NeuACE mice that overexpress ACE in neutrophils. Glomerular injury of NTN in NeuACE mice was attenuated with much less proteinuria, milder histolog-ical injury, and reduced IC deposits, but presented with more glomerular neutrophils in the early stage of the disease. There were no significant defects in T and B cell functions in NeuACE mice. NeuACE neutrophils exhibited enhanced IC uptake with elevated surface expression of Fc gamma RII/III and complement receptor CR1/2. IC uptake in neutrophils was enhanced by NeuACE serum containing ele-vated complement C3b. Given no significant complement activation by ACE, this suggests that neutrophil ACE indirectly preactivates C3 and that the C3b-CR1/2 axis and elevated FccRII/III play a central role in IC elimination by neutrophils, resulting in reduced glomer-ular injury. The present study identified a novel renoprotective role of ACE in glomerulonephritis; elevated neutrophilic ACE promotes elimination of locally formed ICs in glomeruli via C3b-CR1/2 and Fc gamma RII/III, ameliorating glomerular injury. NEW & NOTEWORTHY We studied immune complex (IC)-mediated crescentic glomerulonephritis in NeuACE mice that overex-press ACE only in neutrophils. Such mice show no significant defects in humoral immunity but strongly resist nephrotoxic serum nephritis (less proteinuria, milder histological damage, reduced IC deposits, and more glomerular neutrophils). NeuACE neutro-phils enhanced IC uptake via increased surface expression of CR1/2 and FcgRII/III, as well as elevated serum complement C3b. These results suggest neutrophil ACE as a novel approach to reducing glomerulonephritis.