CHARACTERIZATION OF THE HAN-SPRD RAT MODEL FOR HEREDITARY POLYCYSTIC KIDNEY-DISEASE

The Han:SPRD rat model for inherited polycystic kidney disease (PKD) w as characterized (clinical parameters, morphology, immunohistochemistr y and in situ hybridization). Homozygous animals died of uremia after three to four weeks with severe cystic transformation of virtually all nephrons and collecting ducts (serum urea: 616 +/- 195 mg/dl; kidney- to-body weight ratio: > 20%). In heterozygotes, slow progression of th e disease led to death between the 12th and 21st month (median: 17 mon ths; serum urea levels above 200 mg/dl). Kidney enlargement was modera te, and cysts were restricted to the cortex and outer medulla. Immunoh istochemical markers showed that approximately 75% of the cysts were d erived from the proximal tubule. Cystic transformation started in the proximal tubule with a sharp onset of basement membrane alteration and a loss of epithelial differentiation restricted to small focal areas. In these areas, alpha 1(IV) collagen and laminin B1 mRNA were enhance d as revealed by isotopic and non-isotopic in situ hybridization. Fibr oblasts underlying the affected tubular portions were involved in matr ix overexpression resulting in subepithelial accumulation of immunorea ctive collagen IV and laminin. In later stages of cystic transformatio n distal nephron segments were affected as well. A reversal in epithel ial polarity as judged from Na,K-ATPase-immunoreactivity was not obser ved. Renal immunoreactive renin-status was significantly decreased. He matocrit was lowered in heterozygotes (40.4 +/- 5.8 vol% compared to 4 6.7 +/- 1.99 vol% in controls; P < 0.05) and total renal EPO mRNA was reduced to 36 +/- 14% of the mean value of control animals, whereas se rum EPO levels were not significantly altered. We conclude that the Ha n:SPRD rat is a useful model for the study of human ADPKD since both d iseases are similar in several aspects. The model is particularly suit able for the study of epithelial-mesenchymal interactions at the begin ning of tubular cystic transformation.