Renal hypertrophy in streptozotocin diabetic rats: Role of proteolytic lysosomal enzymes

Abstract

Renal protein mass increases in diabetic renal hypertrophy. Accretion of protein may be the result of increased protein synthesis and/or decreased protein degradation. The lysosomal proteases, cathepsins B and L, are key enzymes in cellular protein catabolism. To evaluate the role of protein degradation in diabetic renal hypertrophy, the activities of cathepsins B and L were measured in microdissected proximal tubule segments and in kidney cortex homogenates. In rats four and ten days following induction of diabetes by streptozotocin, the kidney weight was increased and the cathepsin activities were reduced in proximal tubule segments. Treatment with insulin prevented both changes. The liver weight in diabetic rats was decreased and the activity of cathepsins B and L was increased, while the activity in kidney cortex was reduced. This excluded that diabetes per se may be accompanied by decreased cathepsin activities independent of organ hypertrophy. Renal hypertrophy as a cause rather than as the consequence of reduced cathepsin activities was excluded by the finding of unchanged cathepsin activities in proximal tubule segments from rats with compensatory renal hypertrophy four days and ten days following unilateral nephrectomy. Decreased activities of cathepsins B and L may reflect decreased intracellular protein degradation. Decreased protein breakdown in proximal tubules may contribute to diabetic renal hypertrophy. In agreement with this interpretation are the results from rats six months following induction of diabetes. Renal hypertrophy is complete at that time. No further accretion of protein occurs and the cathepsin activities in the proximal tubule were not different from controls.

Albuminuria in patients with type 1 diabetes is directly linked to changes in the lysosome-mediated degradation of albumin during renal passage.

“…Our finding of a reduced fragmentation ratio of albumin in diabetes may correspond in part to decreased lysosomal activity and/or intracellular trafficking to and from the lysosome. This finding is consistent with findings in other studies that have shown that enzymes specifically associated with lysosomes have decreased activity in diabetes (22)(23)(24). However, it is possible that this change in enzyme activity only affects the size of the fragments excreted and not the quantity.…”

Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C.

“…Renal lysosome activity. While lysosomal activity was decreased in diabetes, which is in agreement with other studies (41,42), it was not normalized by RAM. This finding is the most striking feature of the observations on lysosomal activi t y, for it means that a decrease in renal lysosomal activity is not required for the prevention of albuminuria.…”

Renal proteinases and kidney hypertrophy in experimental diabetes

“…This notion is consistent with earlier observations in diabetic animals where reduced renal proteolytic activity [7,8] and lower activities of lysosomal enzymes such as cathepsins L and B [9,10] and cathepsin D [11] have been reported. Reduced proteinase activity in turn may lead to hypertrophy and matrix accumulation, as it has been demonstrated that inhibition of lysosomal pro-teinases does suppress intracellular protein breakdown by up to 70 % [12].…”