Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice

Hanning You, Ting Gao, Wesley M. Raup-Konsavage, Timothy K. Cooper, Sarah K. Bronson, W. Brian Reeves, Alaa S. Awad

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Abstract

Inflammation is a central pathophysiologic mechanism that contributes to diabetes mellitus and diabetic nephropathy. Recently, we showed that macrophages directly contribute to diabetic renal injury and that pharmacological blockade or genetic deficiency of chemokine (C-C motif) receptor 2 (CCR2) confers kidney protection in diabetic nephropathy. However, the direct role of CCR2 in kidney-derived cells such as podocytes in diabetic nephropathy remains unclear. To study this, we developed a transgenic mouse model expressing CCR2 specifically in podocytes (Tg[NPHS2-Ccr2]) on a nephropathy-prone (DBA/2J) and CCR2-deficient (Ccr2-/-) background with heterozygous Ccr2+/- littermate controls. Diabetes was induced by streptozotocin. As expected, absence of CCR2 conferred kidney protection after nine weeks of diabetes. In contrast, transgenic CCR2 overexpression in the podocytes of Ccr2-/- mice resulted in significantly increased albuminuria, blood urea nitrogen, histopathologic changes, kidney fibronectin and type 1 collagen expression, podocyte loss, and glomerular apoptosis after nine weeks of streptozotocin-induced diabetes. Interestingly, there was no concurrent increase in kidney macrophage recruitment or inflammatory cytokine levels in the mice. These findings support a direct role for CCR2 expression in podocytes to mediate diabetic renal injury, independent of monocyte/macrophage recruitment. Thus, targeting the CCR2 signaling cascade in podocytes could be a novel therapeutic approach for treatment of diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)671-682
Number of pages12
JournalKidney International
Volume91
Issue number3
DOIs
StatePublished - Mar 1 2017

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CCR Receptors
Podocytes
Kidney
Diabetic Nephropathies
Wounds and Injuries
Macrophages
Albuminuria
Experimental Diabetes Mellitus
Blood Urea Nitrogen
Streptozocin
Collagen Type I
Fibronectins
Transgenic Mice
Monocytes
Diabetes Mellitus
Pharmacology
Apoptosis
Cytokines
Inflammation

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

You, Hanning ; Gao, Ting ; Raup-Konsavage, Wesley M. ; Cooper, Timothy K. ; Bronson, Sarah K. ; Reeves, W. Brian ; Awad, Alaa S. / Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice. In: Kidney International. 2017 ; Vol. 91, No. 3. pp. 671-682.
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Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice. / You, Hanning; Gao, Ting; Raup-Konsavage, Wesley M.; Cooper, Timothy K.; Bronson, Sarah K.; Reeves, W. Brian; Awad, Alaa S.

In: Kidney International, Vol. 91, No. 3, 01.03.2017, p. 671-682.

Research output: Contribution to journalArticle

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