Obese Zucker rat: potential role of intraglomerular proteolytic enzymes in the development of glomerulosclerosis.

The obese Zucker rat is a classic model of non-immune-mediated spontaneous focal glomerulosclerosis. An early morphological hallmark of glomerular damage in the obese Zucker rat is a mesangial expansion, which precedes and mediates the development of glomerular damage in these animals. This study was designed to investigate whether there might be a reduced activity of glomerular proteinases in kidneys of obese Zucker rats, thereby being involved in the pathogenesis of mesangial expansion, which is mainly due to protein overloading. In fact, we found a decreased proteinase activity in ultrasonically destroyed isolated glomeruli obtained by a differential sieving technique in obese Zucker rats compared with their lean littermates. This held true at acid as well as at neutral pH and could be confirmed when proteinase activity was related to DNA instead of protein. When investigating the glomerular cathepsin B content--this is a lysosomal enzyme with acid pH optimum, which is involved in the degradation of glomerular structural as well as filtered plasma proteins--we found a significantly increased level in the kidneys of obese Zucker rats. Hence, the intraglomerular proteinase activity is reduced in the face of enhanced glomerular content of at least lysosomal proteinases. The underlying reason for this depressed activity remains to be established. We propose that reduced activities of intraglomerular proteinases may be important in the pathogenesis of mesangial matrix expansion in obese Zucker rats, an important initiating hallmark of glomerulosclerosis in this model.