Abstract: TH-PO233

Reduced Heat Shock Protein 90α/Endothelial Nitric Oxide Synthase Interaction in the Heart Contributes to Cardiovascular Injury in the AKI to CKD Transition

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Amador-Martinez, Isabel, Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM and INNSZ, Mexico City, Mexico
  • Pérez-villalva, Rosalba, Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM and INNSZ, Mexico City, Mexico
  • Bobadilla, Norma, Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM and INNSZ, Mexico City, Mexico
  • Barrera-Chimal, Jonatan, Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM and INNSZ, Mexico City, Mexico
Background

Acute kidney injury (AKI) is a recognized risk factor for chronic kidney disease (CKD) development. CKD is associated with cardiovascular alterations and the associated mechanisms remain largely unexplored. CKD patients display reduced nitric oxide (NO) levels. The endothelial nitric oxide synthase (eNOS) is regulated by phosphorylation and by its interaction with proteins such as heat shock protein 90α (Hsp90α). We investigated some modifications in the eNOS activation pathway that occur in the heart during the AKI to CKD transition.

Methods

We included 50 male Wistar rats that were divided into sham surgery (n=25) or rats subjected to bilateral renal ischemia-reperfusion (IR) of 45 min (n=25). The rats were studied at 1, 2, 3, 4 or 5 months post-surgery (n=5). Urinary protein excretion was monitored every month. After each experimental period, plasma creatinine, renal blood flow, mean arterial pressure levels and heart and renal weights were determined. The apical part of the heart was snap frozen for western blot analyses.

Results

CKD progression in the IR group was characterized by proteinuria that went from 26.5±8 at month-1 to 127.6±24 mg/24h at month-5. The renal dysfunction was only manifested after five months of follow-up as shown by a 50% increase in the plasma creatinine levels and a 30% reduction in the renal blood flow. In contrast, heart hypertrophy was observed since the 4th month after IR, as evidenced by a 24% increase in the heart/body weight ratio. Heart dysfunction and fibrosis were determined by a significant increase in brain natriuretic peptide and collagen I levels, respectively (p<0.05). Moreover, an increase in the phosphorylation of eNOS at threonine 495 (inactivating eNOS) was observed. This effect was associated with reduced eNOS/Hsp90α interaction.

Conclusion

The AKI to CKD transition is characterized by cardiac hypertrophy, dysfunction and fibrosis, even before the renal dysfunction is manifested. These alterations were associated with fewer eNOS activation and reduced eNOS/Hsp90α interaction in the heart, which may result in reduced NO bioavailability and endothelial dysfunction.
PAPIIT: IA200117

Funding

  • Government Support - Non-U.S.