title: Macrophages directly mediate diabetic renal injury.
abstract: Monocyte/macrophage recruitment correlates strongly with the progression of renal impairment in diabetic nephropathy (DN), yet their direct role is not clear. We hypothesized that macrophages contribute to direct podocyte injury and/or an abnormal podocyte niche leading to DN. Experiments were conducted in CD11b-DTR mice treated with diphtheria toxin (DT) to deplete macrophages after streptozotocin-induced diabetes. Additional experiments were conducted in bone marrow chimeric (CD11b-DTR→ C57BL6/J) mice. Diabetes was associated with an increase in the M1-to-M2 ratio by 6 wk after the induction of diabetes. Macrophage depletion in diabetic CD11b-DTR mice significantly attenuated albuminuria, kidney macrophage recruitment, and glomerular histological changes and preserved kidney nephrin and podocin expression compared with diabetic CD11b-DTR mice treated with mutant DT. These data were confirmed in chimeric mice indicating a direct role of bone marrow-derived macrophages in DN. In vitro, podocytes grown in high-glucose media significantly increased macrophage migration compared with podocytes grown in normal glucose media. In addition, classically activated M1 macrophages, but not M2 macrophages, induced podocyte permeability. These findings provide evidence showing that macrophages directly contribute to kidney injury in DN, perhaps by altering podocyte integrity through the proinflammatory M1 subset of macrophages. Attenuating the deleterious effects of macrophages on podocytes could provide a new therapeutic approach to the treatment of DN.
authors.affiliation: Penn State Univ., Hershey Medical Center, College of Medicine, Division of Nephrology, H040, 500 Univ. Drive, PO Box 850, BMR Bldg., C5830, Hershey, PA 17033. asa17@psu.edu.
authors.forename: Hanning
authors.initials: H
authors.lastname: You
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: W
authors.initials: W
authors.lastname: Brian Reeves
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D039481:CD11b Antigen; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C113267:nephrin; D013311:Streptozocin; D005947:Glucose
keywords: diabetic nephropathy; macrophages; podocytes