Klotho interacts with various membrane proteins such as receptors for 
transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF). Renal 
expression of klotho is diminished in polycystic kidney disease (PKD). In the 
present study, the effects of klotho supplementation on PKD were assessed. 
Recombinant human klotho protein (10 μg·kg-1·day-1) or a vehicle was 
administered daily by subcutaneous injection to 6-wk-old mice with PKD 
(DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, 
mice were killed, and the kidneys were harvested for analysis. Exogenous klotho 
protein supplementation reduced kidney weight, cystic area, systolic blood 
pressure, renal angiotensin II levels, and 8-epi-PGF2α excretion (P < 0.05). 
Klotho protein supplementation enhanced glomerular filtration rate, renal 
expression of superoxide dismutase, and klotho itself (P < 0.05). Klotho 
supplementation attenuated renal expressions of TGF-β and collagen type I and 
diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of 
rapamycin (P < 0.05). Pathological examination revealed that klotho decreased 
the fibrosis index and nuclear staining of Smad in PKD kidneys (P < 0.05). Our 
data indicate that klotho protein supplementation ameliorates the 
renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the 
present results implicate klotho supplementation in the suppression of 
Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, 
our findings suggest that klotho protein supplementation attenuated fibrosis at 
least partly by inhibiting epithelial mesenchymal transition in PKD.