Autosomal-dominant polycystic kidney disease in the rat

Abstract

Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements of the pathogenesis of this disease in heterozygotes and homozygotes from birth to advanced disease. Heterozygous male rats developed slowly progressive renal cystic disease with interstitial fibrosis and azotemia seen by six months of age. Female heterozygotes developed slowly progressive renal cystic disease, but did not develop interstitial fibrosis or azotemia. Epithelial cells lining cyst cavities showed various degrees of morphologic immaturity. Cyst walls also developed basement membrane thickening, especially in areas of cellular immaturity, suggesting an interrelationship between this basement membrane thickening and cellular dedifferentiation. Thickened basement membranes were associated with increased immunoreactivity for type IV collagen, laminin, and fibronectin. Homozygous rats developed massive renal enlargement, marked azotemia, and died near three weeks of age. Renal c-myc proto-oncogene expression was elevated in homozygous cystic infants and in adult heterozygotes. In situ hybridization showed high levels of c-myc mRNA in cyst epithelia, suggesting abnormal regulation of cellular proliferation in the cells lining cysts, as seen in other models of PKD. The Han:SPRD rat is the only well-documented animal model of inherited PKD with an autosomal-dominant inheritance pattern and appears to have several features which resemble human ADPKD.

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

“…The autosomal dominant mutation in the rat model, Han:SPRD-cy, which is considered a model for human ADPKD, displayed highly elevated levels of renal c-Myc in cystic epithelia from a young age (97). The hepatocyte nuclear factor-1β (Hnf-1β), which directly modulates expression of the orthologous Pkd2 gene and the Pkhd1 gene responsible for autosomal recessive PKD, produce upon inactivation a mouse model with diabetes and renal cysts.…”

Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease

“…All of the normal rats and Cy͞ϩ rats studied were males. The Cy͞ϩ Han:SPRD rat develops clinically detectable PKD by 8 weeks of age as evidenced by a doubling of the two-kidney͞total body weight ratio (2K͞TBW) compared with ϩ͞ϩ rats (2,4). A colony of Han:SPRD rats was established in our animal care facility from a litter that was obtained from the Polycystic Kidney Program at the University of Kansas Medical Center.…”

“…The heterozygous Han:SPRD rat exhibits many of the features of ADPKD in humans (2), including autosomal dominant inheritance and relatively slow progression to end-stage renal failure with uremia, hypertension, and anemia. The Han:SPRD rat is a suitable and well documented animal model of polycystic kidney disease (PKD) even though the disease is not caused by a defect in the PKD1 or PKD2 genes (3-5) (6).…”

Laminin 5 Regulates Polycystic Kidney Cell Proliferation and Cyst Formation

“…Morphological anomalies of the cyst-surrounding ECM have been described in human and animal models of polycystic kidney disease. Pericystic ECM appears thickened and multilaminated in the earliest detectable cysts (10,11). Cystic epithelial cells produce an abnormal basement membrane and have an abnormal proliferative response to ECM proteins (12)(13)(14).…”