Renal enlargement in polycystic kidney disease (PKD) is caused by the proliferation of mural epithelial cells and transepithelial fluid secretion into the cavities of innumerable cysts. Arginine vasopressin (AVP) stimulates the proliferation of human PKD cells in vitro via cAMP-dependent activation of the B-Raf/MEK (MAPK/ERK kinase/extracellular signalregulated kinase (ERK) pathway. ERK activity is elevated in cells that line the cysts in animals with PKD, and AVP receptor antagonists reduce ERK activity and halt disease progression. For suppression of the effect of AVP physiologically, water intake was increased in PCK rats, a model of PKD, and the effect on renal morphology, cellular mechanism, and function was determined. The addition of 5% glucose in the drinking water increased fluid intake approximately 3.5-fold compared with rats that received tap water. In PCK rats, increased water intake for 10 wk reduced urinary AVP excretion (68.3%), and urine osmolality fell below 290 mOsmol/kg. High water intake was associated with reduced renal expression of AVP V2 receptors (41.0%), B-Raf (15.4%), phosphorylated ERK (38.1%), and proliferating cell nuclear antigen-positive renal cells (61.7%). High water intake reduced the kidney/body weight ratio 28.0% and improved renal function. Taken together, these data demonstrate that water intake that is sufficient to cause persistent water diuresis suppresses B-Raf/MEK/ERK activity and decreases cyst and renal volumes in PCK rats. It is suggested that limiting serum AVP levels by increased water intake may be beneficial to some patients with PKD.

Abstract:A polycystic kidney rat model is being established from a Crj:CD (SD) rat strain. Unlike existing animal models of polycystic kidney disease, this mutant rat has a completely polycystic liver. Mating experiments revealed that the phenotype is controlled by an autosomal recessive gene. We propose that this gene be tentatively called the "rpc" gene. Key words: polycystic kidney, polycystic liver, rat Polycystic kidney disease (PKD) is a hereditary disorder that comes in two forms, adult polycystic kidney disease (APKD), and infantile polycystic kidney disease (IPKD). The adult type is an autosomal dominant polycystic kidney disease (ADPKD) and the infant type is an autosomal recessive polycystic kidney disease (ARPKD). Although many spontaneously occurring polycystic kidney mouse models have been established [1,3,4,8,10,12,13], the Cy rat [2,5,6,11] and the chin rat [9] are the only rat models. At Charles River Japan Inc., we have identified a female rat with polycysts on both the kidney and liver derived from an ongoing colony of Crj:CD (SD) rats. Development of a PKD model animal (hereinafter referred to as the PCK rat) with polycysts on both the kidney and liver was initiated by sib mating offspring of the female animal. Continuous sib mating since 1996 has led to the establishment of a rat model for PKD via an inbred strain originating from the Crj:CD (SD) rat, which is now in its twelfth generation. During this period, characteriza- (Received 27 April 1999 / Accepted 14 September 1999)Address corresponding: M. Katsuyama, Charles River Japan Inc., 10210-6, Tana, Sagamihara, Kanagawa 229-1124, Japan tion of the PCK rat and mating experiments with other strains were also performed, the results of which are reported here.The animal rooms were maintained at a temperature of 19-25°C, humidity of 40-80% with a 12 hr lightdark cycle (06:00-18:00). The animals were given ad libitum access to commercial feed CRF-1 (Oriental yeast Co., Ltd.) and tap-water. Body weight was measured every week from 3 to 111 weeks of age, and survival rate was documented during a general examination of the condition of the animals. The bilateral kidneys and liver were weighed at 5, 15, 25 and 35 weeks of age, and compared with that of the original Crj:CD (SD) rat strain. For histopathological examination, kidney and liver were fixed with 10% formalin, and according to standard procedures, were then paraffin sliced, HE stained, and examined by microscopy. In order to analyze the mode of inheritance, F3-F5 generation pck rats were mated with Crj:CD (SD) rats, bred in a room separate to that of PCK rats, and F344/DuCrj rats. Off-

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