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Abstract: SA-PO775

Full-Length Klotho and Secretase BACE1 Are Upregulated in Human Hearts From Patients With Advanced CKD

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Narayanan, Gayatri, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Halim, Arvin, 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
  • Lu, Tzongshi, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Lim, Kenneth, Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Klotho is an anti-aging protein that has demonstrated remarkable cardiovascular-protective effects. Klotho-deficient mice develop extensive cardiovascular disease that resembles advanced CKD patients; conversely Klotho supplementation rescues this phenotype. Klotho is cleaved into several soluble isoforms that constitute its KL1 and/or KL2 ectodomains by proteases ADAM10, ADAM17, and BACE1. To-date, the expression profile and natural history of Klotho and its regulatory enzymes locally in hearts from patients with CKD is largely undefined. Herein, we performed molecular phenotyping of the local Klotho hormonal system in explanted human donor hearts from patients with CKD.

Methods

We analyzed human left ventricular tissues from advanced CKD donors (hemodialysis, HD; n=19), patients with hypertension with preserved renal function (HTN; n=11), and healthy controls (CON, n=19) collected in the Cardiovascular Aging in CKD (CAIN) cohort. Hearts were subjected to gross pathologic and molecular analysis, including Masson’s Trichrome staining, immunohistochemistry and immunoblotting.

Results

HD and HTN hearts exhibited significantly higher heart weight relative to body surface area (BSA) compared to CON hearts (p<0.001). HD hearts had significantly thicker left ventricular walls compared to CON hearts (p<0.007). There was greater fibrosis staining in HD hearts compared to HTN (p<0.008) and CON hearts (p<0.001). Significantly, HD hearts exhibited greater upregulation of full-length Klotho compared to HTN (p<0.008) and CON hearts (p<0.002). There was no significant difference in full-length Klotho expression between HTN and CON hearts (p=0.7). Interestingly, we did not detect KL1 and KL2 isoforms in human hearts. Moreover, HD hearts exhibited increased BACE1 (p<0.02) compared to HTN and CON hearts. There were no significant differences in ADAM10 or ADAM17 expression in hearts between the three groups (p>0.1).

Conclusion

Full-length Klotho and BACE1 are upregulated in hearts from advanced CKD patients. These results suggest that increased local Klotho expression may be an adaptive response in advanced CKD. Cleavage of myocardial Klotho may be driven by BACE1 in diseased hearts from patients with CKD. Further studies to elucidate the mechanisms and regulation of myocardial Klotho are warranted.

Funding

  • NIDDK Support