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Klotho interacts with various membrane proteins such as receptors for transforming growth factor (TGF)-beta and insulin-like growth factor (IGF) to alter their function. Renal expression of klotho is diminished in chronic kidney disease. In the present study, the effects of klotho supplementation on polycystic kidney disease (PKD) model were assessed.Recombinant human klotho protein (10 μg/kg/day) or vehicle was administered daily by subcutaneous injection to 6 week-old PKD (DBA/2-pcy) mice. Blood pressure was measured by tail-cuff methods. After 2 months, mice were killed by over-dose of anesthesia and the kidneys were harvested for the analysis.Exogenous klotho protein supplementation reduced right (1.24 ± 0.10 vs. 0.84 ± 0.09 g, p < 0.01) and left kidney weight (1.19 ± 0.10 vs. 0.88 ± 0.06 g, p < 0.01), cystic area (51 ± 5 vs. 34 ± 4 %, p < 0.05), systolic blood pressure (110 ± 3 vs. 101 ± 2 mmHg, p < 0.05) and 8-epi-prostaglandin F2alpha excretion (354 ± 86 vs. 100 ± 35 ng/day, p < 0.01) without changes in body weight. Creatinine clearance in klotho-treated PKD mice was higher than the untreated (1.01 ± 0.08 vs. 0.51 ± 0.04 ml/min/g.kidney.wt, p < 0.01). Klotho supplementation reduced plasma angiotensin II levels (459 ± 76 vs 217 ± 31 fmol/ml, p < 0.05) without significant changes in renal angiotensin II concentrations. Exogenous klotho protein supplementation improved renal expression of superoxide dismutase (SOD), as well as renal klotho expression itself (p < 0.01 for each). Klotho supplementation reduced renal expressions of fibronectin and collagen I (p < 0.05 for each), and diminished renal abundance of phosphorylated Akt and mTOR (p < 0.05 for each). Pathological examination revealed that klotho reduced fibrosis index and nuclear staining of Smad3 in PKD kidneys.The present data indicate that klotho supplementation reduces blood pressure in association with ameliorating renin-angiotensin system in PKD mice. Furthermore, our results are consistent with the notion that klotho inhibits IGF signaling, inducing SOD to reduce oxidative stress and suppressing Akt-mTOR signaling to decrease abnormal cystic growth in PKD mice. Finally, the present findings suggest that klotho inhibits TGF-beta signaling through Smad to attenuate fibrosis. The present data provide translational evidence to examine whether klotho supplementation is the treatment of choice for PKD patients resistant to AVP antagonist.