The effect of oral protease administration in the rat remnant kidney
model
Šebeková K.1, Dämmrich J.2,
Krivošíková Z. 1, Heidland A.3
1 Clinic of Pharmacotherapy, Institute of Preventive and
Clinical Medicine, Bratislava, Slovakia
2 Institute of Pathology, University of Würzburg, Germany
3 Department of Internal Medicine, University of Würzburg,
Germany
Research in Experimental Medicine 1999, Vol. 199, No. 3, December
1999, pp. 177-188-(A20511)
PZ 16 (5-09-2)
Abstract
It has been demonstrated that intraperitoneal administration of
proteolytic enzymes ameliorates the progression of renal diseases in
various animal models. In the present study, we employed the rat
remnant kidney model to study the effectiveness of oral
administration of proteases. Twenty male Wistar rats underwent sham
operation (CTRL), while 25 were subjected to 5/6 nephrectomy (5/6
NX). Rats were randomised into placebo (PL) (2 ml tap water/day by
gavage), or Phlogenzym® (E; fixed mixture of trypsin 2.42
mg, bromelain 4.54 mg, and rutosid 5.04 mg added as antioxidant, in
2 ml tap water daily by gavage) treated group. Duration of the study
was 45 days. Rats were pair-fed. Enzyme treatment exerted salutary
effects on various functional and morphological parameters.
Proteinuria was higher in both 5/6 NX group rats throughout the
study. Administration of proteases ameliorated its rise effectively
(data at sacrifice: CTRL-PL 6.27±1.25, CTRL-E 9.27±0.99, 5/6 NX-PL
74.04±21.33, 5/6 NX-E 39.09±7.93 mg/ 24 h; P<0.01). Increased
urinary excretion of the fibrogenic cytokine transforming growth
factor (TGF-b 1) was improved, too (CTRL-PL 0.349±0.051,
CTRL-E 0.693±0.230, 5/6 NX-PL 3.044±0.540, 5/6 NX-E 1.390±0.238 ng/m
mol creatinine; P<0.05). At sacrifice, tubulointerstitial fibrosis
was less pronounced in E-treated rats. Correspondingly, the volume
fraction of tubulointerstitial tissue in the renal cortex was
improved in 5/6 NX-E rats (CTRL-PL 9.9±0.2, CTRL-E 10.0±0.2, 5/6
NX-PL 17.9±1.8, 5/6 NX-E 13.8±0.9%; P<0.05). The protein/DNA ratio
in isolated glomeruli and tubules, as an estimate of glomerular
matrix accumulation and hypertrophy of tubules, was enhanced in 5/6
NX groups and a tendency towards lower values was observed after E
treatment. Renal function as evaluated by serum creatinine and urea
levels was not influenced by the enzyme therapy. No between-group
differences in blood pressure were observed. In summary, oral
administration of proteolytic enzymes improved proteinuria and
urinary TGF-b 1 excretion, as well as the severity of
tubulointerstitial fibrosis without signs of toxicity.
Key words: Rat remnant kidney model - Proteases -
Renal fibrosis - TGF-b1 - Proteinuria