Nephrology Dialysis Transplantation, Vol 12, Issue 5 1001-1006, Copyright © 1997 by Oxford University Press
I Ebihara, T Nakamura, Y Tomino and H Koide
Background. We previously reported that mRNA levels
for extracellular matrix (ECM) components and endothelin (ET)-1 are
upregulated in glomeruli of puromycin aminonucleoside (PAN) nephrosis.
Angiotensin-converting enzyme (ACE) inhibitors are effective in
experimental models of renal injury, including PAN nephrosis. This study
was designed to assess whether the glomerular expression of mRNA for ECM
components, ET-1, metalloproteinases (MMP), and a tissue inhibitor of
metalloproteinases (TIMP) is modulated by a specific endothelin receptor A
antagonist (FR139317) or angiotensin-converting enzyme inhibitor
(enalapril) in PAN-injected rats. Methods. Animals
were divided into six groups. Group 1 consisted of PAN-injected rats given
no treatment. In group 2, PAN-injected rats were given enalapril 35 mg/l.
In group 3, PAN-injected rats were given an intraperitoneal injection of
FR139317. Group 4 consisted of saline-injected rats given no treatment. In
group 5, saline-injected rats were given enalapril. In group 6,
saline-injected rats were given FR139317. We prepared glomerular RNA and
performed Northern blot analysis in all groups.
Results. In PAN nephrosis, glomerula mRNA levels for
&agr;1 (IV) collagen chain, laminin B1 and B2 chains, ET-1, MMP-2 and
TIMP-1 increased at the peak of proteinuria on day 8 and then decreased to
the control level by day 20, whereas those for &agr;1 (I) and
&agr;1 (III) collagen chains, MMP-1, MMP-3 and GAPDH showed little
change in PAN nephrosis throughout the experimental periods. In contrast,
mRNA levels for heparan sulphate proteoglycan (HSPG) decreased on day 8 and
then increased to the control level by day 20. Both enalapril and FR139317
attenuated the increases in mRNA levels for &agr;1 (IV) collagen chain
(P <0.01), laminin chains
(P < 0.01), and ET-1 (P
<0.01), and attenuated the decreases in mRNA levels for HSPG
(P < 0.01) in glomeruli of PAN-injected rats.
Enalapril had little effect on increased glomerular mRNA levels for MMP-2
and TIMP-1 in PAN nephrosis, whereas FR139317 attenuated the increases in
glomerular mRNA levels for MMP-2 (P < 0.01) and
TIMP-1 (P < 0.01).
Conclusions. These data suggest that the beneficial
effects of enalapril and FR139317 may be related to modulation of
glomerular mRNA expression of ECM components and ET-1 and that these agents
may follow a different mechanism in regulating the glomerular mRNA
expression for MMP-2 and TIMP-1 in PAN nephrosis.
Keywords: endothelin receptor; angiotensin-converting
enzyme; extracellular matrix; metalloproteinase
PRELIMINARY REPORTS
Effect of a specific endothelin receptor A antagonist and an angiotensin-converting enzyme inhibitor on glomerular mRNA levels for extracellular matrix components, metalloproteinases (MMP) and a tissue inhibitor of MMP in aminonucleoside nephrosis
Division of Nephrology, Department of Medicine, Koto Hospital, Tokyo, Japan; Juntendo University School of Medicine, Tokyo, Japan/Correspondence to H Koide, Division of Nephrology, Department of Medicine, Koto Hospital, 6-8-5 Ojima, Koto-ku, Tokyo 136, Japan
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