The development of an age-dependent glomerulosclerosis and proteinuria was investigated in two strains of rats in a model of moderate hypertension comparing rats of the Milan Hypertensive Strain (MHS) with rats of the Milan Normotensive Strain (MNS). Serum creatinine, urinary protein excretion, renal morphology (light-and electronmicroscopy) and morphometry of the media thickness of the intrarenal arteries and of the thickness of the glomerular basement membrane were studied in 2-to 16-month-old MHS and MNS rats. Serum creatinine did not differ between MNS and MHS rats in any age group. MNS rats developed a significant proteinuria which coincided with a glomerulosclerosis in about 22% of the glomeruli at 13 to 16 months. In contrast, urinary protein excretion in MHS rats remained stable during the entire observation period; glomerulosclerosis occurred only in 3% of the glomeruli at 13 to 16 months. As a consequence of hypertension media thickness of intrarenal arteries of MHS rats significantly exceeded that of MNS rats, in the interlobular arteries already at 2 months and in the arcuate arteries at 13 to 16 months. In contrast, thickness of the glomerular basement membrane of MHS rats never exceeded that of MNS rats. From these data we conclude, that glomeruli of MHS rats may be protected against the development of an age-dependent glomerulosclerosis and proteinuria. Further support for this conclusion may also be derived from recent experiments showing that the tubuloglomerular feedback sensitivity is significantly higher in MHS than in MNS rats (41).