Role of proteinases in renal hypertrophy and matrix accumulation

Abstract Graded compensatory renal growth was induced either by unilateral (UNX) or 5/6 nephrectomy (5/6-NX). Over the experimental period of 16 weeks, kidney weight increased by 59% in SHAM animals, while the remaining kidney in UNX rats more than doubled its initial weight. The hypertrophic response was most pronounced in the remnant kidney after 5/6-NX with a four fold increment in kidney weight. Morphologically glomerular volume increased moderately after UNX(+27%), while 5/6-NX was associated with marked glomerular hypertrophy (+87%). Significant focal sclerosis was found in 11% of glomeruli in the remaining kidney after UNX. By contrast 83% of glomeruli were sclerosed in the remnant kidney after 5/6-NX. In parallel, there was a significant increase in the glomerular protein/DNA ratio (+23%) in 5/6-NX but not in UNX animals. These glomerular alterations were associated with lower glomerular cysteine and metalloproteinase activities (collagenase, −57%; gelatinase, −49%) in 5/6-NX rats, while UNX rats had normal glomerular proteinase activities. In terms of tubular proteinases, cathepsin activities were significantly lower in UNX rats (cath. L+B, −38%; cath. B, −37%; cath. H, −27%) and more so after 5/6-nephrectomy (cath. L+B, −72%; cath. B, −73%; cath. H, −73%), while metalloproteinase activities were only reduced in 5/6-NX rats (collagenase, −35%; gelatinase, −58%). These findings demonstrate that kidney hypertrophy is associated with reductions in renal proteinase activities. After UNX, which leads to tubular hypertrophy and mild glomerular sclerosis, only tubular cysteine proteinase activities were suppressed. In contrast, in the 5/6-NX model, which is associated with hypertrophic and sclerotic alterations both at the glomerular and tubular levels, pronounced reductions in glomerular and tubular cysteine as well as metalloproteinase activities were observed.