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Renal protective effect of TCV-116 in stroke-prone spontaneously hypertensive rats
1Department of Pharmacology, Osaka City University Medical School, Japan.
Abstract:
We examined the effects of TCV-116, a non-peptide selective AT1 receptor antagonist, on cellular phenotype and on the expression of the transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given vehicle or TCV-116 (10 mg/kg/day) by gastric gavage for 10 weeks (from the age of 22 to 32 weeks). Renal mRNA levels were measured by Northern blot analysis. In vehicle-treated 32-week-old SHRSP, urinary albumin excretion per 24 h was about 26-fold greater than that in age-matched Wistar-Kyoto (WKY) rats, and the mRNA levels of renal TGF-beta 1, fibronectin and collagen types I and III in SHRSP were all several-fold higher than those in WKY. Immunohistochemical studies showed the prominent presence of alpha-smooth muscle actin-expressing glomerular cells in SHRSP, in contrast to their absence in WKY. Treatment of SHRSP with TCV-116 decreased urinary albumin excretion and renal mRNA levels for TGF-beta 1 and for the above-mentioned extracellular matrix components. TCV-116 prevented the phenotypic modulation of glomerular cells in SHRSP. These results suggest that AT1 receptor antagonists may have powerful renal protective effects.
Insights
TCV-116, an AT1 receptor antagonist, reduced kidney damage in hypertensive rats by lowering albuminuria and key gene expression. This suggests AT1 receptor antagonists offer significant renal protection.
Area of Science:
- Nephrology
- Pharmacology
- Hypertension Research
Background:
- Stroke-prone spontaneously hypertensive rats (SHRSP) exhibit significant renal damage, including increased albuminuria and elevated expression of transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix genes.
- These changes are associated with phenotypic modulation of glomerular cells, indicated by alpha-smooth muscle actin expression.
Purpose of the Study:
- To investigate the renal protective effects of TCV-116, a selective AT1 receptor antagonist, in SHRSP.
- To assess the impact of TCV-116 on cellular phenotype, TGF-beta 1, and extracellular matrix gene expression in the kidneys of SHRSP.
Main Methods:
- SHRSP were treated with vehicle or TCV-116 (10 mg/kg/day) for 10 weeks.
- Renal mRNA levels of TGF-beta 1, fibronectin, and collagen types I and III were quantified using Northern blot analysis.
- Immunohistochemistry was employed to evaluate glomerular cell phenotype, specifically alpha-smooth muscle actin expression.
Main Results:
- Vehicle-treated SHRSP showed a 26-fold increase in albuminuria compared to Wistar-Kyoto rats, with significantly higher renal mRNA levels for TGF-beta 1, fibronectin, and collagen.
- SHRSP kidneys exhibited prominent alpha-smooth muscle actin-expressing glomerular cells, unlike in Wistar-Kyoto rats.
- TCV-116 treatment significantly decreased urinary albumin excretion and suppressed the elevated renal mRNA levels of TGF-beta 1 and extracellular matrix components in SHRSP.
- TCV-116 effectively prevented the phenotypic modulation of glomerular cells in SHRSP.
Conclusions:
- TCV-116 demonstrates potent renal protective effects in SHRSP.
- AT1 receptor antagonism may be a valuable therapeutic strategy for mitigating kidney damage in hypertensive conditions.