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 language | English |
|---|---|
| Pages (from-to) | 960-968 |
| Number of pages | 9 |
| Journal | Diabetes |
| Volume | 60 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2011 |
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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 journal › Article
}
TY - JOUR
T1 - Activation of peroxisome proliferator-activated receptor δ inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice
AU - Matsushita, Yuichi
AU - Ogawa, Daisuke
AU - Wada, Jun
AU - Yamamoto, Noriko
AU - Shikata, Kenichi
AU - Sato, Chikage
AU - Tachibana, Hiromi
AU - Toyota, Noriko
AU - Makino, Hirofumi
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79952400627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79952400627&partnerID=8YFLogxK
U2 - 10.2337/db10-1361
DO - 10.2337/db10-1361
M3 - Article
C2 - 21270242
AN - SCOPUS:79952400627
VL - 60
SP - 960
EP - 968
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -