title: Late onset of Ccl2 blockade with the Spiegelmer mNOX-E36-3'PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice.
abstract: Diabetic kidney disease is associated with monocyte chemoattractant CC chemokine ligand 2 (CCL2)-dependent glomerular and interstitial macrophage recruitment. In addition, nephropathy is delayed in Ccl2 mutant diabetic mice. However, whether the late onset of therapeutic Ccl2 blockade modulates the progression of advanced diabetic nephropathy remains unknown. We addressed this question by antagonizing Ccl2 with mNOX-E36-3'PEG, an anti-Ccl2 L-enantiomeric RNA aptamer (ie, a Spiegelmer), which binds murine Ccl2 and blocks the recruitment of ex vivo-labeled macrophages to the kidneys of db/db mice with type 2 diabetes. We injected mNOX-E36-3'PEG subcutaneously at a dose of 50 mg/kg three times per week into uninephrectomized (1K) db/db mice with advanced glomerulopathy from 4 to 6 months of age. mNOX-E36-3'PEG reduced the number of glomerular macrophages by 40% compared with nonfunctional (control) Spiegelmer-treated 1K db/db mice. This result was associated with protection from diffuse glomerulosclerosis and significantly improved the glomerular filtration rate. mNOX-E36-3'PEG also reduced renal Ccl2 mRNA and protein expression compared with control Spiegelmer-treated 1K db/db mice of the same age. Together, the late onset of therapeutic Ccl2 blockade, eg, with specific Spiegelmers, offers protection from diffuse glomerulosclerosis in type 2 diabetic db/db mice and, thus, may represent a novel therapeutic strategy for advanced glomerulosclerosis.
authors.affiliation: Nephrological Center,Medical Policlinic, University of Munich, Munich, Germany.
authors.forename: Volha
authors.initials: V
authors.lastname: Ninichuk
authors.forename: Sebastian
authors.initials: S
authors.lastname: Clauss
authors.forename: Onkar
authors.initials: O
authors.lastname: Kulkarni
authors.forename: Holger
authors.initials: H
authors.lastname: Schmid
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Ewa
authors.initials: E
authors.lastname: Radomska
authors.forename: Dirk
authors.initials: D
authors.lastname: Eulberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Buchner
authors.forename: Norma
authors.initials: N
authors.lastname: Selve
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000209:etiology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D052157:Aptamers, Nucleotide; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C528578:NOX-E36-3'PEG, mouse; D012333:RNA, Messenger; D054390:Receptors, CCR2; D016212:Transforming Growth Factor beta