Imidapril improves L-NAME-exacerbated nephrosclerosis with TGF-β1 inhibition in spontaneously hypertensive rats

Objective This study was designed to investigate whether chronic angiotensin-converting enzyme (ACE) inhibition prevents hypertensive glomerular injury and inhibits increases in the mRNA levels and immunohistological expression of the apoptosis inducer caspase-3, and transforming growth factor (TGF)-beta1 during prolonged nitric oxide synthase (NOS) inhibition with N-G-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Methods and results For 3 weeks, we studied three groups of 20-week-old male SHR: a control group, a L-NAME group, and a group treated with L-NAME and the ACE inhibitor imiclapril. L-NAME rats developed severe hypertensive nephrosclerosis with significantly elevated blood pressure, markedly increased urinary protein excretion and serum creatinine levels, and more severe glomerulosclerosis and tubulo-interstitial changes. Levels of TGF-beta1 mRNA in the renal tissue was also significantly increased in L-NAME rats compared with control SHR. Addition of imidapril significantly lowered blood pressure, inhibited nephrosclerosis and attenuated the mRNA level of TGF-beta1 in comparison with L-NAME/SHR. Histologically, the glomerular cell apoptosis labeling index, terminal doxynucleotidil transferase-mediated dUTP nick-end labeling of fragmented DNA (TUNEL) and active caspase-3, and TGF-beta1 positive areas were also reduced by imidapril. Conclusion These data suggest that imidapril prevents glomerular and arteriolar damages and renal functions, through inhibiting both TGF-beta1 production and apoptosis induction.