Activation of peroxisome proliferator-activated receptor δ inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice

Yuichi Matsushita, Daisuke Ogawa, Jun Wada, Noriko Yamamoto, Kenichi Shikata, Chikage Sato, Hiromi Tachibana, Noriko Toyota, Hirofumi Makino

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

OBJECTIVE - Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-δ has been shown to improve insulin resistance, adiposity, and plasma HDL levels. Several studies have reported that activation of PPARδ is atheroprotective; however, the role of PPARδ in renal function remains unclear. Here, we report the renoprotective effects of PPARδ activation in a model of streptozotocin-induced diabetic nephropathy. RESEARCH DESIGN AND METHODS - Eight-week-old male C57BL/6 mice were divided into three groups: 1) nondiabetic control mice, 2) diabetic mice, and 3) diabetic mice treated with the PPARd agonist GW0742 (1 mg/kg/day). GW0742 was administered by gavage for 8 weeks after inducing diabetes. RESULTS - GW0742 decreased urinary albumin excretion without altering blood glucose levels. Macrophage infiltration, mesangial matrix accumulation, and type IV collagen deposition were substantially attenuated by GW0742. The gene expression of inflammatory mediators in the kidney cortex, such as monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN), was also suppressed. In vitro studies demonstrated that PPARd activation increased the expression of anti-inflammatory corepressor B-cell lymphoma-6, which subsequently suppressed MCP-1 and OPN expression. CONCLUSIONS - These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPARδ agonists and support the concept that PPARδ agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy.

Original languageEnglish
Pages (from-to)960-968
Number of pages9
JournalDiabetes
Volume60
Issue number3
DOIs
Publication statusPublished - Mar 2011

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Peroxisome Proliferator-Activated Receptors
Diabetic Nephropathies
Streptozocin
Anti-Inflammatory Agents
Osteopontin
Chemokine CCL2
Kidney Cortex
Co-Repressor Proteins
Collagen Type IV
Adiposity
B-Cell Lymphoma
Cytoplasmic and Nuclear Receptors
Inbred C57BL Mouse
Insulin Resistance
Blood Glucose
Albumins
Research Design
Macrophages
Kidney
Gene Expression

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Activation of peroxisome proliferator-activated receptor δ inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice. / Matsushita, Yuichi; Ogawa, Daisuke; Wada, Jun; Yamamoto, Noriko; Shikata, Kenichi; Sato, Chikage; Tachibana, Hiromi; Toyota, Noriko; Makino, Hirofumi.

In: Diabetes, Vol. 60, No. 3, 03.2011, p. 960-968.

Research output: Contribution to journalArticle

Matsushita, Yuichi ; Ogawa, Daisuke ; Wada, Jun ; Yamamoto, Noriko ; Shikata, Kenichi ; Sato, Chikage ; Tachibana, Hiromi ; Toyota, Noriko ; Makino, Hirofumi. / Activation of peroxisome proliferator-activated receptor δ inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice. In: Diabetes. 2011 ; Vol. 60, No. 3. pp. 960-968.
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AU - Shikata, Kenichi

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