The pck rat: a new model that resembles human autosomal dominant polycystic kidney and liver disease.

BACKGROUND: The pck rat is a recently identified model of polycystic kidney disease (PKD) and liver disease (PLD) that developed spontaneously in the rat strain Crj:CD/SD. Its pattern of inheritance is autosomal recessive. METHODS: To characterize this new model, we studied pck rats derived from F9 breeding pairs from Charles River Japan and control Sprague-Dawley rats. Blood and tissues (kidneys, liver, and pancreas), obtained from these rats at 1, 7, 21, 70, and 182 days of age, were used for biochemical determinations, light and electron microscopy, and immunohistochemistry. RESULTS: The pck rats develop progressive cystic enlargement of the kidneys after the first week of age, and liver cysts are evident by day 1. The renal cysts developed as a focal process from thick ascending loops of Henle, distal tubules, and collecting ducts in the corticomedullary region and outer medulla. Flat and polypoid epithelial hyperplasia were common in dilated tubules and cysts. Apoptosis was common and affected normal, as well as dilated tubules, but less frequently cysts lined by flat epithelium. The basement membranes of the cyst walls exhibited a variety of alterations, including thinning, lamellation, and thickening. Focal interstitial fibrosis and inflammation were evident by 70 days of age. Segmental glomerulosclerosis and segmental thickening of the basement membrane with associated effacement of the podocyte foot processes were noted in some rats at 70 days of age. The PKD was more severe in male than in female pck rats, as reflected by the higher kidney weights, while there was no gender difference in the severity of the PLD. Mild bile duct dilation was present as early as one day of age. With age, it became more severe, and the livers became markedly enlarged. Even then, however, there was only a mild increase in portal fibrosis, without formation of fibrous septae. Slight elevations of plasma blood urea nitrogen levels were detected at 70 and 182 days of age. CONCLUSIONS: The pck rat is a new inherited model of PKD and PLD with a natural history and renal and hepatic histologic abnormalities that resemble human autosomal dominant PKD. This model may be useful for studying the pathogenesis and evaluating the potential therapies for PKD and PLD. The identification of the pck gene may provide further insight into the pathogenesis of autosomal dominant PKD.

Renal concentration of alpha-tocopherol: dependence on gender and lack of effect on polycystic kidney disease in Han:SPRD rats.

A gender-associated dimorphism, with males being more severely affected than females, has been observed in autosomal dominant polycystic kidney disease, acquired renal cystic disease, and the renal cystic disease of the Han:SPRD rat. A recent study has suggested that gonadal hormones may be responsible for this dimorphism. Because gonadal hormones have an effect on the concentration of alpha-tocopherol in the liver and adrenal glands and because recent studies indicate that oxidative stress may be important in the pathogenesis of polycystic kidney disease, we wanted to determine whether the renal concentration of alpha-tocopherol is higher in female than in male rats and whether this difference accounts for the gender dimorphism of polycystic kidney disease in Han:SPRD rats. At 3 weeks of age, male and female heterozygous cystic (cy/+) rats were divided into three groups fed a vitamin E-deficient diet or the same diet supplemented with either 65 IU or 10,000 IU alpha-tocopherol/kg laboratory chow. At 8 weeks of age, blood samples and kidneys were obtained for determinations of plasma creatinine and urea, renal concentration of alpha-tocopherol and glutathione, kidney weights, and histomorphometric analysis. Female rats had higher renal concentrations of alpha-tocopherol and less severe renal cystic disease, as reflected by plasma creatinine and urea values, kidney weight corrected by body weight, and histomorphometric analysis, than male rats. The difference in renal alpha-tocopherol concentration, however, could not account for the different severity of the renal cystic disease, because depletion or enrichment of vitamin E in the diet had marked effects on the renal concentration of alpha-tocopherol without affecting the severity of the renal cystic disease. Cy/+ rats had higher renal concentrations of alpha-tocopherol than +/+ animals, possibly reflecting a disturbance of redox metabolism associated with polycystic kidney disease. Renal concentrations of glutathione were unaffected by the vitamin E content of the diet. Although these results do not support the use of vitamin E in the treatment of polycystic kidney disease, observations in the Han:SPRD rat may or may not be relevant to human polycystic kidney disease.

Aggravation of polycystic kidney disease in Han:SPRD rats by buthionine sulfoximine.

The administration of ammonium chloride or of sodium or potassium bicarbonate has marked effects on the development of polycystic kidney disease (PKD) in Han:SPRD rats. Because of the possibility that these effects are mediated by changes in redox metabolism, the aim of this study was to determine whether depletion of glutathione, the most abundant and important cellular thiol and scavenger of reactive oxygen species, would affect the development of PKD in this animal model. +/+ and cy/+ Han:SPRD rats were treated with: (1) L-buthionine(S,R)-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione; (2) glutathione monoethyl ester (GME), a compound that is known to increase the intracellular levels of glutathione; or (3) BSO and GME. Treatment with these drugs was started at 3 wk of age, and the animals were killed at 6 or 8 wk of age. Renal levels of oxidized glutathione were significantly higher in cy/+ than in +/+ rats, whereas no significant differences in reduced glutathione were detected. The administration of BSO caused a marked reduction in the levels of glutathione. The administration of GME caused a significant increase in the levels of glutathione at 2 h, but not at 12 h, after the administration. The increase in the renal levels of glutathione 2 h after the administration of GME was less in the rats treated with BSO than in the rats not receiving this drug, indicating that in part the increase in glutathione level was due to de novo synthesis. BSO-induced glutathione depletion was accompanied by a marked aggravation of the renal cystic disease, as reflected by kidney weights, histological scores, and plasma urea concentrations. However, the administration of GME did not lessen the cystic disease and did not reverse the effects of BSO. The transient effect of GME administration and the simultaneous increases in the levels of cysteine and oxidized glutathione, in addition to reduced glutathione, may explain the lack of protection by GME. These data support the notion that changes in redox metabolism may affect the development of PKD.