Taxol inhibits progression of congenital polycystic kidney disease.
Polycystic kidney diseases (PKD) are the most common hereditary diseases of the human kidney and account for ten per cent of patients requiring renal transplantation or dialysis. Renal cyst formation has been attributed to enhanced cell proliferation, unbalanced cell death, abnormal targeting of membrane proteins, aberrant kidney development and tubular obstruction, but there is no treatment that blocks the formation and enlargement of renal cysts. We have now developed an in vitro model of spontaneous cyst formation that distinguishes polycystic kidney epithelium from its normal counterpart. Inhibitors of DNA, RNA and protein synthesis did not prevent in vitro cyst formation, but this was reversibly inhibited by ouabain, amiloride and the microtubule-specific agents colchicine, vinblastine and taxol. The cpk mouse is a well-characterized recessive PKD model and we find that cpk/cpk mice develop PKD and die from uraemia by 4-5 weeks of age, but when treated weekly with taxol they survive for more than 200 days with minimal loss of renal function, show limited collecting-dust cyst enlargement, and attain adult size. Our results indicate that the microtubule cytoskeleton has a central role in the pathogenesis of PKD in cpk mice and that taxol may also be useful in treating human PKD.
Woo
D D
DD
Department of Medicine, UCLA School of Medicine 90024-1689.
Miao
S Y
SY
Pelayo
J C
JC
Woolf
A S
AS
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000187:drug effects; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D017239:Paclitaxel / Q000627:therapeutic use*; D007690:Polycystic Kidney Diseases / Q000151:congenital* / Q000401:mortality / Q000517:prevention & control*
D017239:Paclitaxel