Alteration of growth-related proto-oncogene expression in diabetic glomeruli by a specific endothelin receptor A antagonist.
BACKGROUND
The early phase of glomerular growth in diabetic rats is accompanied by increased c-fos and c-jun expression. The renal endothelin (ET)-1 mRNA levels increased with the progression of diabetic nephropathy. This study was designed to assess whether glomerular mRNA expression of growth-related proto-oncogenes in diabetic rat glomeruli is affected by a specific ET receptor A antagonist, FR139317.


METHODS
Diabetes was produced by streptozotocin (STZ) injection. Animals were divided into four groups: (1) untreated diabetic rats (n = 25); (2) FR139317-treated diabetic rats (n = 20); (3) control non-diabetic rats (n = 20); and (4) FR139317-treated controls (n = 20). FR139317 treatment was continued for 24 weeks. c-myc, c-fos, c-jun and proliferating cell nuclear antigen (PCNA) mRNA expression in rat glomeruli from each group (n = 7) at 4, 12 and 24 weeks after STZ or saline injection was evaluated.


RESULTS
Glomerular mRNA levels for c-myc, c-fos, c-jun and PCNA in group 1 increased with the progression of diabetic nephropathy (24 weeks: c-myc, 4.6-fold; c-fos, 3.8-fold; c-jun, 4.2-fold; and PCNA, 4.4-fold). FR139317 treatment attenuated increases in glomerular mRNA levels of these genes (24 weeks, c-myc, 0.4-fold; c-fos, 0.4-fold; c-jun, 0.5-fold; and PCNA, 0.4-fold) in group 2. However, FR139317 did not affect mRNA levels in control glomeruli.


CONCLUSIONS
These data suggest that FR139317 may protect against glomerular injury of diabetes in rats by reducing mRNA levels of growth-related genes.
Nakamura
T
T
Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Ebihara
I
I
Tomino
Y
Y
Koide
H
H
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000503:physiopathology*; D065128:Endothelin Receptor Antagonists; D015870:Gene Expression; D007211:Indoles / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000254:growth & development / Q000503:physiopathology*; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D007211:Indoles; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C079574:FR 139317