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Alteration of growth-related proto-oncogene expression in diabetic glomeruli by a specific endothelin receptor A
T Nakamura1, I Ebihara, Y Tomino
1Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan.
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.
Insights
The endothelin receptor A antagonist FR139317 reduced the expression of growth-related genes in diabetic rat glomeruli, suggesting a protective effect against diabetic nephropathy.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic nephropathy is associated with increased glomerular growth and expression of proto-oncogenes like c-fos and c-jun.
- Renal endothelin (ET)-1 mRNA levels rise with diabetic nephropathy progression.
Purpose of the Study:
- To investigate the effect of the ET receptor A antagonist FR139317 on glomerular mRNA expression of growth-related proto-oncogenes in diabetic rats.
Main Methods:
- Diabetes was induced in rats using streptozotocin (STZ).
- Animals were divided into untreated diabetic, FR139317-treated diabetic, control, and FR139317-treated control groups.
- mRNA levels of c-myc, c-fos, c-jun, and PCNA were measured in glomeruli at 4, 12, and 24 weeks.
Main Results:
- Diabetic rats showed significantly increased glomerular mRNA levels for c-myc, c-fos, c-jun, and PCNA with disease progression.
- FR139317 treatment attenuated these increases in diabetic rats.
- FR139317 did not affect mRNA levels in control non-diabetic rats.
Conclusions:
- FR139317 may protect against diabetic glomerular injury by downregulating growth-related genes.
- Targeting the ET receptor A pathway could be a therapeutic strategy for diabetic nephropathy.