Protease administration decreases enhanced transforming growth factor-beta 1 content in isolated glomeruli of diabetic rats.
Overproduction of transforming growth factor (TGF)-beta 1 messenger RNA is of fundamental importance in the pathogenesis of diabetic nephropathy. In vitro studies have recently shown that the serine protease trypsin diminishes the enhanced TGF-beta 1-expression induced by advanced glycation end products. Moreover, proteolytic enzymes may accelerate the removal of TGF-beta 1 from renal tissue via a protease-induced activation of alpha 2-macroglobulin (alpha 2M). This activation results in the binding of numerous cytokines, including TGF-beta 1 and is followed by enhanced plasma clearance of the protease alpha 2M-cytokine complex. In the present study in streptozotocin-diabetic rats we investigated whether the administration of Phlogenzym, a fixed combination of the proteases trypsin and bromelain combined with the antioxidant rutosid, modulates renal hypertrophy and the formation of TGF-beta 1 in isolated glomeruli. Three weeks after induction of diabetes, renal hypertrophy developed with an enhanced kidney/body weight ratio. When compared with normal rats, an elevated content of intraglomerular TGF-beta 1 (44.25 +/- 21.9 vs. 71.1 +/- 23.4 ng/microgram DNA, p < 0.05) as well as fibronectin (2.62 +/- 0.49 vs. 3.42 +/- 0.62 ng/microgram DNA, p < 0.05) was observed. In the diabetic rats, treatment with intraperitoneal proteases prevented the rise of intraglomerular TGF-beta 1 content (34.9 +/- 22.2 ng/microgram DNA, p < 0.01) and attenuated the rise of fibronectin (3.03 +/- 1.12 ng/microgram DNA NS). Furthermore, a decrease in the kidney/body weight ratio (p < 0.01) was achieved. Protease administration did not affect blood glucose concentration and was without visible adverse effects.
Paczek
L
L
Transplantation Institute, Warsaw School of Medicine, Nowogrodzka Street, 02-006 Warsaw, Poland.
Gaciong
Z
Z
Bartlomiejczyk
I
I
Sebekova
K
K
Birkenmeier
G
G
Heidland
A
A
D000818:Animals; D001835:Body Weight; D001963:Bromelains / Q000494:pharmacology*; D002401:Cathepsin B / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004338:Drug Combinations; D010450:Endopeptidases / Q000008:administration & dosage*; D005353:Fibronectins / Q000378:metabolism; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D012431:Rutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014357:Trypsin / Q000494:pharmacology*; D000511:alpha-Macroglobulins / Q000378:metabolism
D004338:Drug Combinations; D005353:Fibronectins; C119937:Phlogenzym; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000511:alpha-Macroglobulins; D012431:Rutin; D001963:Bromelains; D010450:Endopeptidases; D014357:Trypsin; D002401:Cathepsin B; D017364:Collagenases