【文章名】Late onset of Cc12 blockade with the spiegelmer mNOX-E36-3 ' PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice
[摘要]：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 Cc12 mutant diabetic mice. However, whether the late onset of therapeutic Cc12 blockade modulates the progression of advanced diabetic nephropathy remains unknown. We addressed this question by antagonizing Cc12 with mNOX-E36-3'PEG, an anti-Cc12 L-enantiomeric RNA aptamer (ie, a Spiegelmer), which binds murine Cc12 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) Spiegelmertreated 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 Cc12 mRNA and protein expression compared with control Spiegelmer-treated 1K db/db mice of the same age. Together, the late onset of therapeutic Cc12 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.
