The effect of oral protease administration in the rat remnant kidney model

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 rutozid 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-beta 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/mumol 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-beta 1 excretion, as well as the severity of tubulointerstitial fibrosis without signs of toxicity.

Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

“…Proteolytic enzyme treatments have been exploited therapeutically in various experimental nephropathies for two decades 9,10 . Proteolytic enzymes administrated i.p., i.v.…”

Interstitial fibrosis in mice with overload proteinuria: Deficiency of TIMP-1 is not protective

“…This response is six to seven weeks decreased renal fibrosis in the rat remnant kidney model and the Goldblatt-hypertension not unique to the kidney but also characterizes fibrosis in other organs such as the liver [44]. Indeed, TIMP-1 model [37,38]. However, fibrogenesis, particularly at some extrarenal sites, has been associated with a net is already known to have many other effects that are not dependent on its ability to inhibit metalloproteinases.…”

Oxidative stress, advanced glycation end products and residual renal function in the rat model of unilateral ureteral obstruction: effects of phlogenzym and losartan

“…Effects of the treatment. We compared the established beneficial effects of the administration of losartan with the potential beneficial action of Phlogenzym and their combination on the function of the CL kidney, from the point of interference with AGEs and oxidative status, since: 1) inhibitors of converting enzyme and ARBs ameliorate the alterations induced by UUO [27]; 2) the experimental and clinical data suggest that ARBs may attenuate oxidative stress and formation of AGEs [13,28,29] 16], and in models of progressive renal diseases administration of Phlogenzym exerted beneficial effects of on renal function and morphology [17,18]. Contralateral kidney (Table).…”

“…In studies on pig proximal tubular cells (LLC-PK1) trypsin prevented the AGEs-induced cell hypertrophy and accumulation of AGEs [15,16]. In rodents administration of proteases improved the course of various renal diseases [17,18]. Whether administration of proteases interferes with AGEs and oxidative stress in vivo remains unclear.…”