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Abstract: SA-PO766

Klotho Protein Supplementation Retards Renal Injury in 5/6-Nephrectomized Rats

Session Information

  • CKD: Mechanisms - III
    November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Takenaka, Tsuneo, International University of Health and Welfare, Sanno Hospital, Tokyo, Japan
  • Kobori, Hiroyuki, Tulane University Hypertension and Renal COE, New Orleans, Louisiana, United States
  • Inoue, Tsutomu, Saitama Medical University, Iruma-gun, Saitama, Japan
  • Ishii, Naohito, Kitasato University, Sagamihara, KANAGAWA, Japan
  • Hayashi, Matsuhiko, Kawakita General Hospital, Suginami-ku, TOKYO, Japan
Background

We have previously reported that ronacaleret, a calcilytic agent, retards renal injury by increasing endogenous klotho expression in remnant kidney model (Am J Physiol Renal Physiol. 2015;309:F216-26). Recent studies have demonstrated that FGF23 transduces its signal using klotho as co-receptor to increase renal abundance of Egr-1 and phosphorylated ERK, both of which may control the exprerssion of bone morphogenetic protein (BMP) 7.

Methods

In the present study, the effects of exogenous klotho protein supplementation on renal injury was compared between two groups of rats (n=6 for each group); 5/6-nephrectomized Wister rats (Nx), those treated with klotho (20 μg/kg/day) (Nx+K). Three months later, rats were killed with over-anesthesia, and harvested remnant kidney for analysis.

Results

Albuminuria was lower in Nx+K (42±6 mg/day) than Nx group (132±14 mg/day, p<0.05). Glomerular filtration rate and serum calcium were similar between 2 groups. However, fractional phosphate excretion was increased in Nx+K group (13±2 %) than Nx group (7±1 %, p<0.05). Serum phosphate (8.1±0.3 mg/dl (Nx+K) vs 9.8±0.3 mg/dl (Nx), p<0.05).and FGF23 (361±17 pg/ml (Nx+K) vs 480±31 pg/ml (Nx), p<0.05) were reduced in Nx+K group. RT-PCR analysis revealed that compared to Nx (p<0.05), renal expressions of klotho (1.8 fold) and BMP7 (1.7 fold) were elevated in Nx+K group. In contrast, renal expression of TGF-β in Nx+K group (2.1±0.2) was lower than Nx group (3.2±0.3, p<0.05). Western blot analyses showed that renal abundance of Egr-1 and phosphorylated ERK in Nx+K group was higher than Nx group. Pathological examination revealed that fibrosis index in Nx+K group was smaller than Nx group, and that endogenous klotho and BMP7 were co-localized in both renal tubular and interstitial cells.

Conclusion

The present data indicate that klotho supplementation reduced albuminuria, serum phosphate and FGF23 in 5/6-nephroctomized rats. Our findings demonstrate that exogenous klotho supplementation prevented the declines in endogenous klotho expression to recover normal FGF23-klotho signaling that facilitates phosphate excretion. Finally, the current results provide the evidence that klotho protein, which inhibits renal fibrosis, counteracts against TGF-β in itself as well as induces BMP7 expression by elevating the abundance of Egr-1 and phosphorylated ERK. in remnant kidney.

Funding

  • Government Support - Non-U.S.