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Autosomal dominant polycystic kidney disease (ADPKD) inherited with an incidence of
1: 1000 is one of the most frequent hereditary disorders in humans and leads to terminal renal failure in approximately 50% of all patients before reaching the age of 60. The development of multiple cysts in all nephron parts characterises the disease. A causal therapy is not available. To date, the most suitable animal model of ADPKD is the PKD/Mhm-rat strain.The aim of this study was to analyse the influence of an altered genetic background on the histopathologic picture of polycystic: kidneys, using the PKI)/M1im-rat model. Furthermore it was to be examined if the paternal or maternal transfer of the PKI)-gene influences the PKDphenotype. Due to the reason that many animals in the study developed a hydronephrosis, the question arose if PKD and hydronephrosis interact.To perform these analyses, a back-cross generation between PKD/Mhm- and BN-rat was produced. The animals of the PKDBN RI-generation (n=742) were sacrificed and examined at the age of 36 days, all other animals used after exclusion from breeding. To gain f
urther information about the unexpected occurrence of hydronephrosis additional BN-rats were mated. Consequently 5 different lines were available for the study:PKDBN RP, PKDBN F1-, PKD/Mhm-, BN- and BNxBN-rats.The analysis of these lines gave the following results: 5,1% of the PKD-positive PKDBN R 1rats expressed suchmassive kidney alterations that have not been observed as yet in the PKD/Mhm (cy/+)rats. 61,7% of the PKDBN RI- and 26,7% of the PKDBN F1-rats surprisingly developed a hydronephrosis, which aggravated the effect of the phenotype of PKD. Itoriginated from the BN-rat. The kidneys of the PKDBN F1-females expressed a significantly weaker degree of PKD than those of pure PKD/Mhm-females at the same age. Almost no regular cysts were developed, instead many dilated tubules with on
ly incompletely thickened tubule walls were found. A connection between the lines and the degree of cystic degeneration could not be shown, meaning no genetic imprinting occurred. A genderdifference was recognised in the PKD phenotype: The disease was significantly more pronounced in the male rats. PKD seemed to influence the expression of hydronephrosis:PKD positive PKDBN Rl-animals more frequently developed hydronephrosis than PKD negative- and pure BN-rats. More animals of the paternal line expressed hydronephrosis than those of the maternal line.The difference in the PKD phenotype between rats of the PKDBN R 1 PKDBN F 1 -generation and the pure PKD (cyl+)-rats suggests the participation of modifying genes in the PKD syndrome. Since the backcross with WOK-rats, in the study of Gretz et al. , did not change the phenotype, possible modifying genes probably originate from the BN-rat. This hypothesis is supported because the kidneys of PKD positive rats on average were more polycystic, if they simultaneously expressed hydronephrosis. It is conceivable that the modifying genes were activated due to the involvement of hydronephrosis. Thus the hydronephrosis gene either represents this modifying gene itself or the rise in pressure - in consequence of hydronephrosis - leads to a regulatory change of the gene expression.Regarding the heredity mode of hydronephrosis the following theses can be raised: Due to the distribution of hydronephrosis in the different generations it could be possible that hydronephrosis is monogenic autosomal recessive inherited in rats that do not carry a mutated gene. But as soon as an animal carries the defective gene though,
independent of the hydronephrosis status of the mother, hydronephrosis development is more frequent, than would be the case in a monogenic autosomal recessive genetic make-up. This phenomenon could be accounted for because PKD conditioned mutations (i.e. hypertension) increase the penetration of hydronephrosis, respectively that PKD associated modifying genes influence hydronephrosis.The analyses of clusterin expression and rate of apoptosis show, that in PKD positive animals that simultaneously expressed hydronephrosis, an aggravation of cell damage (increased expression of clusterin) in the distal tubules and in the urothelium occurred. The rate of apoptosis in these nephron sections were, however, not increased. Thus an increase of cell damage does not necessarily increase apoptosis.re-1
23Furthermore, due to the clusterin positive nephron sections it can be suspected that exactly those nephrons that form cysts in the proximal tubules express clusterin in the distal tubules.Since no cysts are formed in the distal tubules but an increased clusterin expression occurs, the possibility exists that clusterin, functionally mediating a cell-cell-adhesion, here results in a protection.