Abstract: FR-PO996
Therapeutic Targeting of Vascular Calcification by KL1 in a CKD-MBD Rat Model
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Halim, Arvin, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Narayanan, Gayatri, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States
- O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Lim, Kenneth, Indiana University School of Medicine, Indianapolis, Indiana, United States
Background
Vascular calcification is a common complication in patients with CKD that causes arterial stiffening, which can lead to hypertension and adverse cardiac remodeling. Klotho-deficient animal models exhibit a similar vascular calcification phenotype seen in patients with CKD, which can be ameliorated with exogenous administration of full-length Klotho. The KL1 domain of Klotho can be cleaved from full-length Klotho removing its FGF23-binding domain. Studies have shown that KL1 is biologically active, however it is unknown whether KL1 can directly exert anti-calcific effects similar to full-length Klotho.
Methods
Cy/+ male rats were fed a casein-based diet starting at 22 weeks old, and then treated daily with intraperitoneal injections of 50 μg/kg human recombinant KL1 (Cat. No. 100-53, PeproTech; n=6) or vehicle (0.1% bovine serum albumin in 0.9% saline; CKD, n=12) for 5-7 weeks starting at 27 weeks old. Rats were euthanized for tissue collection at 32-34 weeks old. Normal littermates (NL, n=8) were used as a control. Tissue calcification assessment, histology and protein analysis of the aorta were performed.
Results
CKD rats, compared to NL rats, developed elevated BUN (mean±SD: 46.13±9.41 mg/dL vs. 19.44±3.57 mg/dL; P<0.001), creatinine (1.53±0.61 mg/dL vs. 0.44±0.053 mg/dL; P<0.001), plasma phosphate (12.67±4.71 mg/dL vs. 6.17±1.12 mg/dL; P<0.001), decreased eGFR (671.61±463.83 μL/min vs. 2912.01±213.51 μL/min; P<0.001) and increased total kidney weight normalized to body weight (TKW/BW, 13.46±3.36 mg/g vs. 6.69±0.23 mg/g; P<0.001). CKD rats developed significant aortic calcification (62.88±31.22 mg/dL) compared to NL rats (27.69±14.27 mg/dL; P<0.005). Moreover, CKD rats treated with KL1 exhibited significantly reduced aortic calcification (32.5±15.53 mg/dL; P<0.018) and BUN (37.76±1.95 mg/dL; P<0.02) compared to vehicle treated CKD rats. Phosphate (10.99±1.38 mg/dL, P>0.27), creatinine (1.57±0.35mg/dL; P>0.86), eGFR (599.84±190.48 μL/min; P>0.65), and TKW/BW (13.31±2.44 mg/g; P>0.91) in KL1 treated rats did not significantly differ from vehicle treated CKD rats.
Conclusion
KL1 reduces aorta vascular calcification in a rat CKD-MBD model. This suggests that the KL1 domain of Klotho can directly exert cardiovascular protective effects. Further studies are warranted to elucidate the underlying molecular mechanisms.
Funding
- Other NIH Support