EFFECT OF LOVASTATIN ON THE DEVELOPMENT OF POLYCYSTIC KIDNEY-DISEASE IN THE HAN-SPRD RAT

Proliferation of tubular epithelial cells is a major element leading t o cyst formation in Han:SPRD rats with autosomal dominant polycystic k idney disease (PKD), ras proteins are important in the control of rena l cell proliferation, and res gene expression is increased in PKD, Far nesyl pyrophosphate, an intermediate in the conversion of acetyl-CoA t o cholesterol, is required for the activation of ras guanosine triphos phate (GTP)-binding proteins that are important in the execution of se veral cellular functions, including cell proliferation, 3-Hydroxy-3-me thylglutaryl coenzyme A reductase inhibitors, such as lovastatin, redu ce farnesyl production in responsive cells and thereby have potential far ameliorating the accelerated epithelial cell proliferation of PKD. We administered lovastatin to heterozygous (Cy/+) Han:SPRD rats (4 mg /kg/d subcutaneously) from age 4 to 10 weeks, a period of rapid cystic disease progression in these animals, Untreated male Cy/+ rats develo ped larger cystic kidneys and had more severe renal functional impairm ent than females, as reported previously, In males, lovastatin signifi cantly decreased cystic kidney size (referenced to body weight), the v olume density of cysts, and the serum urea nitrogen level 14.5%, 24.4% , and 25.6/%, respectively, The corresponding changes in females were insignificant, and lovastatin had no effect on kidney weight or serum urea nitrogen in homozygous (+/+) normal male animals. On the basis of these results we conclude that lovastatin diminishes the severity of PKD in heterozygous male Han:SPRD rats. (C) 1995 by the National Kidne y Foundation, Inc.