aliskiren and Glomerulonephritis--Membranoproliferative

Certain kidney diseases are associated with complement activation although a renal triggering factor has not been identified. Here we demonstrated that renin, a kidney-specific enzyme, cleaves C3 into C3b and C3a, in a manner identical to the C3 convertase. Cleavage was specifically blocked by the renin inhibitor aliskiren. Renin-mediated C3 cleavage and its inhibition by aliskiren also occurred in serum. Generation of C3 cleavage products was demonstrated by immunoblotting, detecting the cleavage product C3b, by N-terminal sequencing of the cleavage product, and by ELISA for C3a release. Functional assays showed mast cell chemotaxis towards the cleavage product C3a and release of factor Ba when the cleavage product C3b was combined with factor B and factor D. The renin-mediated C3 cleavage product bound to factor B. In the presence of aliskiren this did not occur, and less C3 deposited on renin-producing cells. The effect of aliskiren was studied in three patients with dense deposit disease and this demonstrated decreased systemic and renal complement activation (increased C3, decreased C3a and C5a, decreased renal C3 and C5b-9 deposition and/or decreased glomerular basement membrane thickness) over a follow-up period of four to seven years. Thus, renin can trigger complement activation, an effect inhibited by aliskiren. Since renin concentrations are higher in renal tissue than systemically, this may explain the renal propensity of complement-mediated disease in the presence of complement mutations or auto-antibodies.

Topics: Amides; Chemotaxis; Child; Complement Activation; Complement C3; Complement C3a; Complement C3b; Complement C4; Complement C5a; Complement C5b; Complement Factor B; Complement Factor D; Female; Fumarates; Glomerular Basement Membrane; Glomerulonephritis, Membranoproliferative; Humans; Mast Cells; Renin

Aberrant regulation of an alternative pathway of the complement system could be a therapeutic target of C3 glomerulopathy, including dense deposit disease. In the current issue, Békássy and colleagues provide data on enzymatic conversion of C3 by renin in vitro and on the efficacy of a direct renin inhibitor, aliskiren, on systemic and renal complement activation in patients with dense deposit disease.

Topics: Amides; Complement Activation; Complement C3; Complement Pathway, Alternative; Fumarates; Glomerulonephritis, Membranoproliferative; Humans; Renin