Expression and Function of Peroxisome Proliferator–Activated Receptor-γ in Mesangial Cells

Author:

Nicholas Susanne B.1,Kawano Yasuko1,Wakino Shu1,Collins Alan R.1,Hsueh Willa A.1

Affiliation:

1. From the Department of Medicine, Division of Nephrology (S.B.N.), and Division of Endocrinology, Diabetes, and Hypertension (S.B.N., S.W., A.R.C., W.A.H.), UCLA School of Medicine, Los Angeles, Calif, and Nagasaki University Hospital (Y.K.), Third Department of Internal Medicine, Nagasaki, Japan.

Abstract

Peroxisome proliferator–activated receptor-γ (PPARγ) is a novel nuclear receptor, which enhances insulin-mediated glucose uptake. Ligands to PPARγ are currently used as therapy for type II diabetes. Using Western blot analysis, RNase protection assay, and immunostaining, we identified the presence of PPARγ message and protein in cultured primary rat mesangial cells. Electrophoretic mobility of a labeled PPARγ response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARγ is functional in these cells. The addition of unlabeled PPRE efficiently competed away the PPARγ-PPRE protein complex, confirming specificity of binding of the PPARγ to the PPRE. PPARγ ligands rosiglitazone (1 to 10 μmol/L) and troglitazone (1 to 10 μmol/L) inhibited platelet-derived growth factor–induced DNA synthesis, measured as bromodeoxyuridine incorporation (P <0.01). This inhibition was dose dependent. When administered in antidiabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 3 months (from 687.1 to 137.6 μg urinary albumin/mg creatinine, P <0.05) but did not affect hyperglycemia or blood pressure in this model. This treatment also decreased glomerular plasminogen activator inhibitor-1 (PAI-1) expression. These data suggest that PPARγ activation may directly attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy, or by inhibiting PAI-1 expression. PAI-1 inhibits the activation of plasmin and matrix metalloproteinase, which degrade extracellular matrix in the glomerulus. Excess glomerular PAI-1 allows the accumulation of extracellular matrix, leading to glomerulosclerosis. These results have therapeutic implications for diabetic nephropathy as well as for proliferative mesangial diseases of the kidney.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Internal Medicine

Cited by 116 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3