Summary
IDDM is associated with an increase in kidney size, which is due to cellular hypertrophy and progressive matrix accumulation within the glomerulus and throughout the tubulointerstitium. The present study addressed the potential role of cysteine and metalloproteinases in renal hypertrophy of short-term diabetes. Three weeks after induction of streptozotocin diabetes in rats, intraglomerular gelatinase activity (streptozotocin: 23±4 vs control: 44±3 mU/μg DNA) and cathepsin L + B activity (streptozotocin: 6.7±0.8 vs control: 9.3±0.7 U/μg DNA) were significantly decreased. Insulin treatment completely prevented the decline in glomerular proteinase activity (gelatinase: 37±6 mU/μg DNA; cathepsin L + B: 9.6±0.9 U/μg DNA). In isolated proximal tubules a similar pattern of enzyme activity could be observed. Three weeks of diabetes caused a significant decline in cathepsin L + B activity (streptozotocin: 28±2 vs control: 37±3 U/μg DNA). Insulin treatment again prevented the decline in these tubular proteinase activities. In parallel, kidney weight increased by 22% and glomerular protein/DNA ratio rose by 17% in untreated diabetic rats. Diabetic rats receiving insulin displayed a normal glomerular protein/DNA ratio and the kidney weight was increased by only 5%. These results show that renal hypertrophy of early diabetes is closely associated with a decline in both glomerular and tubular proteinase activity. Adequate insulin substitution prevented renal hypertrophy and the reduction in proteinase activity.
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Abbreviations
- AMC:
-
7-Amino-4-methyl coumarin
- EDTA:
-
ethylene diamine tetra-acetic acid
- PMSF:
-
phenylmethylsulfonyl fluoride
- TGF-β :
-
transforming growth factor-β
- TIMP:
-
tissue inhibitor of metalloproteinases
- GFR:
-
glomerular filtration rate
- IDDM:
-
insulin-dependent diabetes mellitus
References
Mogensen CE, Anderson MJF (1973) Increased kidney size and glomerular filtration rate in early juvenile diabetes. Diabetes 22: 706–712
Mogensen CE, Andersen MJF (1975) Increased kidney size and glomerular filtration rate in untreated juvenile diabetics: normalization by insulin treatment. Diabetologia 11: 221–224
Seyer-Hansen K (1976) Renal hypertrophy in streptozotocin-diabetic rats. Clin Sci Mol Med 51: 551–555
Seyer-Hansen K, Hansen J, Gunderson HJG (1980) Renal hypertrophy in experimental diabetes. A morphometric study. Diabetologia 18: 501–505
Osterby R, Gunderson HJG, Götzsche O, Seyer-Hansen K (1980) The rate of synthesis and breakdown of glomerular basement membrane material at the transition of ‘normal to diabetes’ and ‘diabetes to normal’. Renal Physiol 3: 298–303
Prigent-Sassy C, Bruneval P, Heudes D, Belair MF, Bariety J (1993) Glomerulosclerosis in streptozotocin-induced diabetic rats: absence of increased synthesis of type IV collagen. XXXth Congress EDTA, Glasgow, p 18 (Abstract)
Teschner M, Schaefer RM, Svarnas A, Heidland U, Heidland A (1989) Decreased proteinase activity in isolated glomeruli of streptozotocin diabetic rats. Am J Nephrol 9: 464–469
Lubec G, Leban J, Peyroux J et al. (1982) Reduced collagenolytic activity of rat kidneys with streptozotocin diabetes. Nephron 30: 357–360
Shechter P, Bonner G, Rabkin R (1991) Depressed protein breakdown and cathepsin activity contribute to renal hypertrophy. JASN 2: 297 (Abstract)
Olbricht CJ, Geissinger B (1992) Renal hypertrophy in streptozotocin diabetic rats: role of proteolytic enzymes. Kidney Int 41: 966–972
Nerurkar MA, Satav JG, Katyare SS (1988) Insulin-dependent changes in lysosomal cathepsin D activity in rat liver, kidney, brain and heart. Diabetologia 31: 119–122
Kairallah EA (1985) Quantitative assessment of the contribution of autophagy to intracellular protein breakdown. Biochem Soc Trans 13: 1012–1015
Davies M, Thomas GJ, Martin J, Lovett DH (1988) The purification and characterization of a glomerular-basement-membrane-degrading neutral proteinase from rat mesangial cells. Biochem J 251:419–425
Thomas GJ, Davies M (1989) The potential role of human kidney cortex cysteine proteinases in glomerular basement membrane degradation. Biochem Biophys Acta 990: 246–253
Barrett AJ (1980) Fluorometric assay for cathepsin B and cathepsin H with methylcoumarylamide substrates. Biochem J 187: 909–912
Barrett AJ, Kirschke H (1981) Cathepsin B, cathepsin H and cathepsin L. Meth Enzymol 80: 535–561
Tschesche H, McCartney HW, Fedrowitz J (1981) Gelatinase and collagenase. In: Bergmeyer HU (ed) Methods of enzymatic analysis, pp 155–159 and 239–248
Labarca C, Peigen K (1979) A simple, rapid, and sensitive DNA assay procedure. Anal Biochem 102: 344–352
Smith PK, Krohn RJ, Hermanson GT et al. (1985) Measurement of protein using Bicinochoninic acid. Anal Biochem 150: 76–85
Hostetter TH, Troy JL, Brenner BM (1981) Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int 19: 410–415
Jensen PK, Sandahl Christiansen J, Steven K, Parving HH (1981) Renal function in streptozotocin-diabetic rats. Diabetologia 21: 409–414
Young B, Johnson R, Alpers C, Eng E, Floege J, Couser W (1993) Several early cellular events in glomeruli precede the development of glomerulosclerosis in experimental diabetic nephropathy. XIIth Int Congress Nephrol, Jerusalem 1993, pp 422 (Abstract)
Olbricht CJ, Cannon JK, Garc LC, Tisher CC (1986) Activities of cathepsin B and L in isolated nephron segments from proteinuric and nonproteinuric rats. Am J Physiol 250: F1055-F1062
Seglen PO, Gordon PB, Tolleshaug H (1985) Autophagy and protein degradation in isolated hepatocytes. Biochem Soc Trans 13: 1007–1010
Libby P, Goldberg AL (1978) Leupeptin, a protease inhibitor, decreased protein degradation in normal and diseased muscles. Science 199: 534–536
Neff NT, DeMartino GN, Goldberg AL (1979) The effect of protease inhibitors and decreased temperature on the degradation of different classes of proteins in cultured hepatocytes. J Cell Physiol 101: 439–458
DeMartino GN, Goldberg AL (1978) Thyroid hormones control lysosomal enzyme activities in liver and muscle. Proc Natl Acad Sci USA 196: 1369–1373
Tolnai S, Korecky B (1980) Lysosomal hydrolases in the heterotopically isotransplanted heart undergoing atrophy. J Mol Cell Cardiol 12: 869–890
Kominami E, Tsukahara T, Bando Y, Katunuma N (1985) Distributions of cathepsins B and H in rat tissues and peripheral blood cells. J Biochem 98: 87–93
Ruff RL, Secrist D (1984) Inhibitors of prostaglandin synthesis or cathepsin B prevent muscle wasting due to sepsis in the rat. J Clin Invest 73: 1483–1486
Border WA, Ruoslahti E (1992) Transforming growth f actorβin disease: the dark side of tissue repair. J Clin Invest 90: 1–7
Ignotz RA, Massague J (1986) Transforming growth factor beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem 261: 4337–4345
Bassols A, Massague J (1988) Transforming growth factor β regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans. J Biol Chem 263: 3039–3045
Solem M, Rawson C, Linburg K, Barnes D (1990) Transforming growth factor beta regulates cystatin C in serumfree mouse embryo cells. Biochem Biophys Res Commun 172: 945–951
Edwards DR, Murphy G, Reynolds JJ et al. (1987) Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J 6: 1899–1904
Laiho M, Saksela O, Keski-Oja J (1987) Transforming growth factor-βinduction of type-1 plasminogen activator inhibitor. J Biol Chem 262: 17467–17474
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Schaefer, L., Schaefer, R.M., Ling, H. et al. Renal proteinases and kidney hypertrophy in experimental diabetes. Diabetologia 37, 567–571 (1994). https://doi.org/10.1007/BF00403374
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DOI: https://doi.org/10.1007/BF00403374