Ccl2/Mcp-1 blockade reduces glomerular and interstitial macrophages but does not ameliorate renal pathology in collagen4A3-deficient mice with autosomal recessive Alport nephropathy.
Lack of the alpha3 or alpha4 chain of type IV collagen (COL4) causes autosomal recessive Alport nephropathy in humans and mice that is characterized by progressive glomerulosclerosis and tubulointerstitial disease. Renal pathology is associated with chemokine-mediated macrophage infiltrates but their contribution to the progression of Alport nephropathy is unclear. We found Ccl2 to be expressed in increasing amounts during the progression of nephropathy in Col4a3-deficient mice; hence, we blocked Ccl2 with anti-Ccl2 Spiegelmers, biostable L-enantiomeric RNA aptamers suitable for in vivo applications. Ccl2 blockade reduced the recruitment of ex vivo-labelled macrophages into kidneys of Col4a3-deficient mice. We therefore hypothesized that a prolonged course of Ccl2 blockade would reduce renal macrophage counts and prevent renal pathology in Col4a3-deficient mice. Groups of Col4a3-deficient mice received subcutaneous injections of either an anti-mCcl2 Spiegelmer or non-functional control Spiegelmer on alternate days, starting from day 21 or 42 of age. Glomerular and interstitial macrophage counts were found to be reduced with Ccl2 blockade by 50% and 30%, respectively. However, this was not associated with an improvement of glomerular pathology, interstitial pathology, or of overall survival of Col4a3-deficient mice. We conclude that Ccl2 mediates the recruitment of glomerular and interstitial macrophages but this mechanism does not contribute to the progression of Alport nephropathy in Col4a3-deficient mice.
Clauss
Sebastian
S
Nephrological Center, Medical Policlinic, University of München, Germany.
Gross
Oliver
O
Kulkarni
Onkar
O
Avila-Ferrufino
Alejandro
A
Radomska
Ewa
E
Segerer
Stephan
S
Eulberg
Dirk
D
Klussmann
Sven
S
Anders
Hans-Joachim
HJ
D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005808:Genes, Recessive; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D052157:Aptamers, Nucleotide; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C528578:NOX-E36-3'PEG, mouse