Increased apoptosis of glomerular cells, with progression of glomerulosclerosis, overactivity of the renin-angiotensin system and elevation of glomerular pressure, follows chronic
nitric oxide synthase (NOS) inhibition in spontaneously hypertensive rats (SHR). To gain insight into the regulation of glomerular cell apoptosis in severe
nephrosclerosis, we investigated apoptosis, the expression of proliferative cell
nuclear antigen (
PCNA) in glomeruli, and glomerular morphometric changes in 20-week-old SHR, SHR treated with NOS inhibitor,
NG-nitro-L-arginine methyl ester (
L-NAME; 80 mg/l in
drinking water), and SHR treated with
L-NAME and the
calcium antagonist,
efonidipine (20 mg/kg per day), for 3 weeks. Apoptosis in non-sclerotic glomeruli was quantified by terminal deoxynucleotide
transferase-mediated dUTP nick-end labeling. The increase in systolic blood pressure and the severe
proteinuria with severe
nephrosclerosis induced by chronic NOS inhibition were completely prevented by
efonidipine. Furthermore, the glomerular area and capillary tuft area were markedly increased in rats treated with
efonidipine compared with both control rats (+30 and +42%, respectively, p<0.01) and rats treated with
L-NAME (+35 and +56%, respectively, p<0.01)-treated rats. This
calcium antagonist also significantly inhibited the both increases of the glomerular cell apoptosis index (-72%) and the
PCNA index (+44%), therefore the alteration between apoptosis and proliferation slightly increased the number of glomerular cells (subcapsular, +22%, p<0.01; juxtamedullary, +2%, not significant). Thus, the
calcium antagonist
efonidipine seems to play an important role in the regulation of apoptosis and proliferation of glomerular cells and may be effective in preventing
nephrosclerosis exacerbated by NOS inhibition.