(Hypertension. 2001;37:722.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Expression and Function of Peroxisome Proliferator–Activated Receptor-
in Mesangial Cells
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.
Correspondence to Susanne B. Nicholas, MD, PhD, UCLA School of Medicine, Division of Nephrology and Division of Endocrinology, Warren Hall, Suite 24-130, 900 Veteran Ave, Box 957073, Los Angeles, CA 90095. E-mail sunicholas{at}mednet.ucla.edu
Peroxisome
proliferator–activated receptor-
(PPAR) is a novel
nuclear receptor, which enhances insulin-mediated glucose uptake.
Ligands to PPAR are currently used as therapy for type II diabetes.
Using Western blot analysis, RNase protection assay, and
immunostaining, we identified the presence of PPAR
message and protein in cultured primary rat mesangial
cells. Electrophoretic mobility of a labeled PPAR response element
(PPRE) was retarded in the presence of mesangial cell
nuclear extract, suggesting that PPAR is functional in these cells.
The addition of unlabeled PPRE efficiently competed away the
PPAR-PPRE protein complex, confirming specificity of binding of the
PPAR to the PPRE. PPAR 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 PPAR 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.
Key Words: diabetes mellitus • insulin • mesangium • kidney • albuminuria
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