Suppressed activities of cathepsins and metalloproteinases in the chronic model of puromycin aminonucleoside nephrosis

Glomerulosclerosis and tubulointerstitial fibrosis are the hallmarks of chr onic renal diseases. In the present study, we have investigated the potenti al involvement of various proteinases in these alterations in the model of puromycin aminonucleoside (PAN) nephrosis. Two groups of male Wistar rats w ere given either three or seven injections of PAN (2.0 mg/100 g body weight ) over a 4- and 12-week period, respectively. The two control groups receiv ed saline injections. Activities of cathepsins (B, H and L) were determined in isolated glomeruli and proximal tubules. Moreover, collagenaselike and gelatinaselike activities were analyzed in isolated glomeruli. Three weeks after weekly PAN injection, the rats developed heavy proteinuria (140.8+/-2 2.0 vs. 13.5+/-3.29 mg/day; p<0.001), and at week 11 protein excretion reac hed 606.6+/-23.00 vs. 22.8+/-1.5 mg/day. Renal morphology revealed minimal glomerular mesangial changes at the 4th week after PAN administration. At t he 12th week a marked mesangial matrix accumulation as well as severe tubul ointerstitial infiltration and fibrosis associated with tubular dilation an d atrophy were observed. Glomerular cathepsins B, H, and L and gelatinaseli ke activities decreased at the 4th week after the first PAN injection and r emained at this low level throughout the entire study period. Glomerular co llagenaselike activity decreased at the 4th week (p<0.05) and was still mil dly lower than that of the control group at the 12th week, but without sign ificance. In the isolated proximal tubules, the activities of cathepsins B, H, and L showed the same pattern of decreases as those found in the glomer uli over the whole experimental period. Taken together, our data in the mod el of chronic PAN nephrosis suggest that the suppressed activities of cathe psins as well as the decreased gelatinase- and collagenaselike activities p articipate in the accumulation of extracellular matrix and thereby may cont ribute to the development of glomerulosclerosis and tubulointerstitial fibr osis.