Kidney Week

Abstract: PO1837

Dual Action of β2AR-Agonism Confers Protection Against Heart Failure and Renal Dysfunction via Inotropic and Lusitropic Effects and Normalized Cholesterol Homeostasis in a Mouse Model of Alport Syndrome

Session Information

• Hypertension and CVD: Mechanisms
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• Chahdi, Ahmed, University of Miami School of Medicine, Miami, Florida, United States

Ahmed Chahdi, PhD

• Yousefi, Keyvan, University of Miami School of Medicine, Miami, Florida, United States

Keyvan Yousefi,

• Condor Capcha, Jose M., University of Miami School of Medicine, Miami, Florida, United States

Jose M. Condor Capcha,

• Freundlich, Michael, University of Miami School of Medicine, Miami, Florida, United States

Michael Freundlich,

• Ramic, Melina, University of Miami School of Medicine, Miami, Florida, United States

Melina Ramic,

• Lambert, Guerline, University of Miami School of Medicine, Miami, Florida, United States

Guerline Lambert,

• Shehadeh, Serene, University of Miami School of Medicine, Miami, Florida, United States

Serene Shehadeh,

• Dunkley, Julian C., University of Miami School of Medicine, Miami, Florida, United States

Julian C. Dunkley,

• Lee, Yee-Shuan, University of Miami School of Medicine, Miami, Florida, United States

Yee-Shuan Lee,

• Khan, Aisha, University of Miami School of Medicine, Miami, Florida, United States

Aisha Khan,

• Zeier, Zane, University of Miami School of Medicine, Miami, Florida, United States

Zane Zeier,

• Dykxhoorn, Derek, University of Miami School of Medicine, Miami, Florida, United States

Derek Dykxhoorn,

• Katsoufis, Chryso P., University of Miami School of Medicine, Miami, Florida, United States

Chryso P. Katsoufis,

• Hare, Joshua M., University of Miami School of Medicine, Miami, Florida, United States

Joshua M. Hare,

• Nabity, Mary B., Texas A&M University, College Station, Texas, United States

Mary B. Nabity,

• Rivera, Carolina, University of Miami School of Medicine, Miami, Florida, United States

Carolina Rivera,

• Lymperopoulos, Anastasios, Nova Southeastern University, Fort Lauderdale, Florida, United States

Anastasios Lymperopoulos,

• Webster, Keith A., University of Miami School of Medicine, Miami, Florida, United States

Keith A. Webster,

• Irion, Camila, University of Miami School of Medicine, Miami, Florida, United States

Camila Irion,

• Shehadeh, Lina, University of Miami School of Medicine, Miami, Florida, United States

Lina Shehadeh,

Background

Col4a3^-/-Alport mice present a model of heart failure with preserved ejection fraction (HFpEF) secondary to CKD. HFpEF is characteristically unresponsive to pharmacological intervention. Here, we tested the hypothesis that selective β2AR modulation with salbutamol could alleviate symptoms of CKD and simultaneously augment cardiac function. Secondarily, we investigated the mechanism of actions of such β2AR-mediated therapeutics on cardiac and renal functions.

Methods

Alport mice were injected intraperitoneally with salbutamol or DMSO vehicle as a single bolus of 200µg/dose in short-term studies or daily with 100 µg/dose for 2 weeks long-term. Cardiac and renal functions, cAMP levels, in vivo renal tubular LDL-C uptake and renal histology were evaluated post-injection.

Results

Short-term, salbutamol improved renal function in parallel with decreased LDLR levels and reduced uptake of LDL-C into renal tubules. Long-term, cardiac diastolic function assessed by isovolumetric relaxation time (IVRT), filling pressures (E/E^'), and myocardial performance index, and systolic function reflected by ejection fraction, stroke volume and cardiac output improved significantly in parallel with increased cardiac cAMP. Mechanistically, in the kidney, salbutamol induced IDOL-mediated ubiquitination and subsequent lysosomal degradation of the LDLR via a novel β2AR-mediated, cAMP-independent pathway involving the Rac1/Cdc42 β1PixGEF. β1Pix reversibly sequesters IDOL into a complex with LDLR, thereby blocking the degradation pathway. β2AR stimulation dissipates the complex reactivating IDOL-mediated LDLR degradation thereby re-establishing LDL-C homeostasis and renal function. Using flow cytometry in HEK293T cells, ectopic expression of β1Pix stabilized cell surface LDLR abundance in an IDOL-dependent and PCSK9-independent manner.

Conclusion

β2AR agonism represents a potential treatment strategy to alleviate progression of CKD and heart failure associated with HFpEF phenogroup 3.

Funding

• Other NIH Support