Complement-mediated dysfunction of glomerular filtration barrier accelerates progressive renal injury.
Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload-induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell-derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease.
Abbate
Mauro
M
Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. abbate@marionegri.it
Zoja
Carla
C
Corna
Daniela
D
Rottoli
Daniela
D
Zanchi
Cristina
C
Azzollini
Nadia
N
Tomasoni
Susanna
S
Berlingeri
Silvia
S
Noris
Marina
M
Morigi
Marina
M
Remuzzi
Giuseppe
G
D000818:Animals; D003176:Complement C3 / Q000172:deficiency* / Q000502:physiology; D018450:Disease Progression; D005919:Glomerular Filtration Rate; D008297:Male; D051379:Mice; D051437:Renal Insufficiency / Q000209:etiology*
D003176:Complement C3