Macrophages directly mediate diabetic renal injury

Hanning You, Ting Gao, Timothy K. Cooper, W. Brian Reeves, Alaa S. Awad

Research output: Contribution to journalArticle

57 Scopus citations

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 glomer-ular 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 mac-rophage 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.

Original languageEnglish (US)
Pages (from-to)F1719-F1727
JournalAmerican Journal of Physiology - Renal Physiology
Volume305
Issue number12
DOIs
StatePublished - Dec 15 2013

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Keywords

  • Diabetic nephropathy
  • Macrophages
  • Podocytes

ASJC Scopus subject areas

  • Physiology
  • Urology

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