Tubular cell protein degradation in early diabetic renal hypertrophy.
Renal hypertrophy in diabetes is accompanied by an increase in kidney protein content, which reflects an imbalance between protein synthesis and degradation. This study determines whether altered cellular protein degradation contributes to the imbalance. Diabetes was induced in rats with streptozotocin (55 mg/kg/ip). After 2 or 4 days of diabetes, kidney weight and protein content were measured. Over the 4 days, despite a loss in body weight, kidney wet weight increased by 35% and protein content by 37% in the diabetic rats. Treatment with insulin prevented this increase. Long-lived protein degradation was measured in isolated proximal tubules prelabeled with (14C)valine in vivo. Two days after streptozotocin, protein degradation was depressed by 19% (P < 0.05) and by the fourth day by 27% compared with that in nondiabetic controls (2.6% +/- 0.2 versus 1.9 +/- 0.1% degraded/h; P < 0.01). This was accompanied by a similar diabetes-induced decrease in proximal tubule cathepsin B and L activity. Accordingly, this study provides direct evidence that, in diabetes, tubular cell protein breakdown is depressed and suggests that altered lysosomal cathepsin activity may contribute to this effect. Depressed proteolysis likely contributes to the increase in kidney protein content and hence to diabetic renal hypertrophy.
Department of Medicine, Stanford University, CA.
P
P
Shechter
G
G
Boner
R
R
Rabkin
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002401:Cathepsin B / Q000032:analysis; D056668:Cathepsin L; D002403:Cathepsins / Q000032:analysis; D003546:Cysteine Endopeptidases; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D010450:Endopeptidases; D005260:Female; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008247:Lysosomes / Q000201:enzymology; D009929:Organ Size; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D015431:Weight Loss
D001786:Blood Glucose; D011506:Proteins; D013311:Streptozocin; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534280:Ctsl protein, rat