Dual blockade of the homeostatic chemokine CXCL12 and the proinflammatory chemokine CCL2 has additive protective effects on diabetic kidney disease.

Abstract

Monocyte/ chemoattractant protein-1/chemokine ligand (CCL) 2 and stromal cell-derived factor-1/CXCL12 both contribute to glomerulosclerosis in mice with type 2 diabetes mellitus, through different mechanisms. CCL2 mediates macrophage-related inflammation, whereas CXCL12 contributes to podocyte loss. Therefore, we hypothesized that dual antagonism of these chemokines might have additive protective effects on the progression of diabetic nephropathy. We used chemokine antagonists based on structured l-enantiomeric RNA (so-called Spiegelmers) ie, the CCL2-specific mNOX-E36 and the CXCL12-specific NOX-A12. Male db/db mice, uninephrectomized at the age of 6 weeks, received injections of Spiegelmer, both Spiegelmers, nonfunctional control Spiegelmer, or vehicle from the age of 4 months for 8 weeks. Dual blockade was significantly more effective than monotherapy in preventing glomerulosclerosis. CCL2 blockade reduced glomerular leukocyte counts and renal-inducible nitric oxide synthase or IL-6 mRNA expression. CXCL12 blockade maintained podocyte numbers and renal nephrin and podocin mRNA expression. Consistently, CXCL12 blockade suppressed nephrin mRNA up-regulation in primary cultures of human glomerular progenitors induced to differentiate toward the podocyte lineage. All previously mentioned parameters were significantly improved in the dual-blockade group, which also suppressed proteinuria and was associated with the highest levels of glomerular filtration rate. Blood glucose levels and body weight were identical in all treatment groups. Dual chemokine blockade can have additive effects on the progression of diabetic kidney disease when the respective chemokine targets mediate different pathomechanisms of disease (ie, inflammation and progenitor differentiation toward the podocyte lineage).

• Authors: Murthy N Darisipudi, Onkar P Kulkarni, Sufyan G Sayyed, Mi Ryu, Adriana Migliorini, Costanza Sagrinati, Eliana Parente, Axel Vater, Dirk Eulberg, Sven Klussmann, Paola Romagnani, Hans-Joachim Anders
• Journal: The American journal of pathology (Am J Pathol) Vol. 179 Issue 1 Pg. 116-24 (Jul 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21703397 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Chemokine CCL2
• Chemokine CXCL12
• Interleukin-6
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• NPHS2 protein
• RNA, Messenger
• nephrin
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Blotting, Western
• Cells, Cultured
• Chemokine CCL2 (antagonists & inhibitors, metabolism)
• Chemokine CXCL12 (antagonists & inhibitors, metabolism)
• Diabetes Mellitus, Type 2 (physiopathology)
• Diabetic Nephropathies (metabolism, pathology, prevention & control)
• Glomerular Filtration Rate
• Glomerulonephritis (metabolism, pathology, prevention & control)
• Immunoenzyme Techniques
• Interleukin-6 (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Kidney Glomerulus (metabolism, pathology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Podocytes (metabolism, pathology)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Stem Cells (metabolism)