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.
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, glomerular mRNA levels for alpha 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 alpha 1 (I) and alpha 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 alpha 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.
Ebihara
I
I
Department of Medicine, Koto Hospital, Tokyo, Japan.
Nakamura
T
T
Tomino
Y
Y
Koide
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D018093:Gelatinases / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics*; D007211:Indoles / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000235:genetics*; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D011480:Protease Inhibitors / Q000494:pharmacology; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D019714:Tissue Inhibitor of Metalloproteinases
D000806:Angiotensin-Converting Enzyme Inhibitors; D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006023:Glycoproteins; D007211:Indoles; D011480:Protease Inhibitors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D019714:Tissue Inhibitor of Metalloproteinases; C079574:FR 139317; D011692:Puromycin Aminonucleoside; D004656:Enalapril; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2