1. Klotho supplementation ameliorates blood pressure and renal function in DBA/2-pcy mice, a model of polycystic kidney disease
- Author
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Tsuneo Takenaka, Tsutomu Inoue, Naohito Ishii, Takashi Miyazaki, Hiroyuki Kobori, Akira Nishiyama, Matsuhiko Hayashi, and Hiromichi Suzuki
- Subjects
medicine.medical_specialty ,Physiology ,Injections, Subcutaneous ,medicine.medical_treatment ,Blood Pressure ,Kidney ,urologic and male genital diseases ,Fibroblast growth factor ,Mice ,Insulin-like growth factor ,Internal medicine ,Renin–angiotensin system ,medicine ,Polycystic kidney disease ,Animals ,Myofibroblasts ,Receptor ,Klotho Proteins ,Klotho ,Cells, Cultured ,Glucuronidase ,Polycystic Kidney Diseases ,Chemistry ,Growth factor ,medicine.disease ,Recombinant Proteins ,female genital diseases and pregnancy complications ,Endocrinology ,Female ,Transforming growth factor - Abstract
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-PGF2αexcretion ( 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.
- Published
- 2020