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Third-party-funded project

Title:
The Role of a2u-Globulin in Renal Pathology Induced in Male Rats by Propiverine

Project management at the University of Würzburg:

Participating scientists:

Abstract:
Male and female rats were exposed with feed to 300 and 1000 ppm Propiverine. Group size was 60 rats. Total exposure of rats was conducted for 36 weeks, age of the animals at the start of the study was 4 months. Interim sacrifices of animals (n = 3, every two weeks after the start of the study) from all exposure groups (controls, male and female rats administered 300 and 1000 ppm Propiverine in the diet) were conducted to characterize the time-course of pathological changes in the kidney and kinetics of possible a2u-globulin accumulation. a2u-Globulin was quantified both by a capillary electrophoresis method and by immunohistochemistry. Results on a2u-globulin accumulation were compared to those obtained with a positive control in male rats (4 x 50 mg/kg 2,2,4-trimethylpentane, oral administration).
Propiverine did not induce an increased appearance of pathological lesions in the liver of male or female F344 rats. In the kidney, both male and female rats showed hyaline droplets in the cytosol of proximal tubules and in the nuclei of proximal tubule epithelium cells. The induction of hyaline droplets was dose-dependent and they appeared at a much earlier time-point and at a higher intensity (larger droplets) in male than in female rats. Male rats also exhibited a higher degree of cortical nephropathy (tubular dilatation, cell shedding, sloughing, proteinaceous casts, CPN) as compared to female rats. The degree of cortical nephropathy appeared to be correlated to the dose and duration of Propiverine exposure and to the degree of pathology observed in the glomeruli (glomerulo-nephritis and ?sclerosis). These pathological changes were observed at a much earlier time-point in male rats as compared to female rats exposed to Propiverine. Medullary and papillary changes (tubular dilatation, linear mineralization, casts, hemorrhaging, edema, vacuolization, necrosis) were also observed in higher incidence in Propiverine-treated male rats as compared to Propiverine-treated female rats.
However, the renal pathology induced by Propiverine is not due to the accumulation of a2u-globulin. The hyaline droplets observed in Propiverine treated male and female rats did not contain a2u-globulin. Hyaline droplet formation was also observed in female rats exposed to Propiverine. This observation is also not consistent with the hypothesis that a2u-globulin is involved in the renal pathology induced by Propiverine. a2u-Globulin was also never observed to accumulate in the nucleus of rat kidney cells and the hyaline droplets observed in Propiverine-treated rats were clearly distinct from the male rat specific a2u-globulin. The presence of pelvic pathology, especially transitional epithelium hyperplasia, is also not a typical sign of a2u-globulin induced pathology, preneoplasia or neoplasia.

Key words:
    a2u-Globulin
    Nephrotoxicity

Projekt period: from 07.1999 to 02.2001

Funding institution:
Wirtschaftsunternehmen ( Apogepha Arzneimittel GmbH, Dresden )