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Kidney Week

Abstract: SA-OR076

Heat Shock Proteins Prevent Mitochondrial Dysfunction In Uremic Cardiomyopathy: Results from the CAIN Study

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms


  • Song, Michelle D., Brigham and Women's Hospital, Arlington, Massachusetts, United States
  • Halim, Arvin, Brigham and Women's Hospital, Arlington, Massachusetts, United States
  • Ho, Li-lun, Massachusetts Institute of Technology, Quincy, Massachusetts, United States
  • Hiemstra, Thomas F., University of Cambridge, Cambridge, United Kingdom
  • Lim, Kenneth, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Lu, Tzongshi, Brigham and Women's Hospital, Harvard Medical School, Natick, Massachusetts, United States

Uremic cardiomyopathy is a life-limiting condition that occurs in chronic kidney disease (CKD). Emerging evidence has shown that mitochondrial dysfunction is critical in the pathogenesis of the failing heart. We previously showed that impairment of mitochondrial bioenergetics, fusion and division activities is a cardinal event in heart failure in CKD. Heat Shock Protein (HSP) 70 is an inducible HSP that has been shown to exert self-cytoprotective effects. We previous report that HSP70 prevents vascular calcification in uremic conditions and mitochondrial dysfunction in various stress models. In this study, we hypothesized that induction of HSP70 can prevent mitochondrial dysfunction in the failure heart in CKD.


Human left ventricular tissues collected from advanced CKD on dialysis (n=15) and healthy donors (n=15) were subjected to RNA sequencing, ex vivo. We developed a digital cell sorting study model using deconvolution method to enhance interpretation of heterogenous transcriptomic profiles inherent of mixed-cell type tissue. Primary human cardiac myofibroblast were treated with uremic serum and calcification medium (CM, 5 mM calcium chloride and 5 mM β-glycerolphosphate disodium), in vitro. Cells were placed into an incubator for heat shock treatment (HST) at 43°C for 30 min to induce HSPs.


Our data shows that HSP70, as well as HSP27 and HSP90 were significantly down-regulated in CKD hearts compared to control group (p<0.01). Additionally, cytoprotective mtHSP70 (HSPA9) and the HSP70 co-chaperone, Bcl2 associated Athanogene 1 (BAG1) were highly expressed in healthy control hearts compared to CKD. However, mitochondrial fusion regulation genes MFN1 and OPA1 were down-regulated in CKD hearts (p<0.01). Analysis of primary human cardiac myofibroblast treated with CM and uremic serum revealed the same pattern of changes, in vitro. Induction of HSP70 by HST in cardiac myofibroblasts significantly prevented mitochondrial dysfunction, in vitro (p<0.01).


Our data shows that mitochondrial dysfunction and downregulation of HSPs are involved in the development of uremic cardiomyopathy. Induction of HSP70 prevents mitochondrial dysfunction in cardiac cells under uremic stress. Further studies are critically warranted to investigate therapeutic strategies targeting HSP70 in uremic cardiomyopathy.


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