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Aliskiren inhibits renin-mediated complement activation

Békássy, Zivile D. LU ; Kristoffersson, Ann Charlotte LU ; Rebetz, Johan LU ; Tati, Ramesh LU ; Olin, Anders I. LU and Karpman, Diana LU (2018) In Kidney International
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
aliskiren, children, complement, dense deposit disease, kidney, renin
in
Kidney International
publisher
Nature Publishing Group
external identifiers
  • scopus:85047921035
ISSN
0085-2538
DOI
10.1016/j.kint.2018.04.004
language
English
LU publication?
yes
id
4515f045-9ea9-483f-a3a9-dd06403409ad
date added to LUP
2018-06-14 16:05:40
date last changed
2018-06-15 03:00:03
@article{4515f045-9ea9-483f-a3a9-dd06403409ad,
  abstract     = {<p>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.</p>},
  author       = {Békássy, Zivile D. and Kristoffersson, Ann Charlotte and Rebetz, Johan and Tati, Ramesh and Olin, Anders I. and Karpman, Diana},
  issn         = {0085-2538},
  keyword      = {aliskiren,children,complement,dense deposit disease,kidney,renin},
  language     = {eng},
  month        = {01},
  publisher    = {Nature Publishing Group},
  series       = {Kidney International},
  title        = {Aliskiren inhibits renin-mediated complement activation},
  url          = {http://dx.doi.org/10.1016/j.kint.2018.04.004},
  year         = {2018},
}