Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease.
We have previously demonstrated an increase in proapoptotic caspase-3 in the kidney of Han:SPRD rats with polycystic kidney disease (PKD). The aim of the present study was to determine the effect of caspase inhibition on tubular cell apoptosis and proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 weeks of age and then treated with the caspase inhibitor IDN-8050 (10 mg/kg per day) by means of an Alzet (Palo Alto, CA) minipump or vehicle [polyethylene glycol (PEG 300)] for 5 weeks. The two-kidney/total body weight ratio more than doubled in Cy/+ rats compared with +/+ rats. IDN-8050 significantly reduced the kidney enlargement by 44% and the cyst volume density by 29% in Cy/+ rats. Cy/+ rats with PKD have kidney failure as indicated by a significant increase in blood urea nitrogen. IDN-8050 significantly reduced the increase in blood urea nitrogen in the Cy/+ rats. The number of proliferating cell nuclear antigen-positive tubular cells and apoptotic tubular cells in non-cystic and cystic tubules was significantly reduced in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. On immunoblot, the active form of caspase-3 (20 kDa) was significantly decreased in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. In summary, in a rat model of PKD, caspase inhibition with IDN-8050 (i) decreases apoptosis and proliferation in cystic and noncystic tubules; (ii) inhibits renal enlargement and cystogenesis, and (iii) attenuates the loss of kidney function.
Tao
Yunxia
Y
Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Renal Box C281, 4200 East 9th Avenue, Denver, CO 80262, USA.
Kim
Jun
J
Faubel
Sarah
S
Wu
Joe C
JC
Falk
Sandor A
SA
Schrier
Robert W
RW
Edelstein
Charles L
CL
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D049109:Cell Proliferation; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006579:Heterozygote; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D007690:Polycystic Kidney Diseases / Q000473:pathology; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D002154:Calpain; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002401:Cathepsin B