Kidney Week

Abstract: TH-PO203

Establishing a Mouse Model of Heart Failure with Preserved Ejection Fraction Secondary to CKD

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Lee, Lauren Elizabeth, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Lauren Elizabeth Lee

• Forelli, Nicholas A., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Nicholas A. Forelli, MD

• Mukhi, Dhanunjay, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Dhanunjay Mukhi, PhD

• Arany, Zoltan Pierre, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

Zoltan Pierre Arany, MD, PhD

Background

Chronic kidney disease (CKD) affects 37 million US adults and significantly elevates cardiovascular disease and heart failure (HF) risk, causing ≥50% of CKD mortalities. Proximal tubule cells in CKD and cardiomyocytes in HF exhibit parallel metabolic switches: increased glycolysis reliance and decreased fatty acid oxidation and oxidative phosphorylation reliance. Notably, non-diabetic CKD patients show a correlation of decreased estimated glomerular filtration rate (eGFR) with increased myocardium glucose uptake. It is unknown if CKD contributes to HF by causing cardiac metabolism to be glucose reliant. This has yet to be confirmed in vivo due to no reliable HF-secondary-to-CKD mouse model.

Methods

We placed wild-type 8 wk/old male mice on a 0.2% adenine diet, assessing kidney function (GFR, urine/serum markers, histology) and heart function (echocardiography, serum markers, histology) at 4 and 8 weeks. At 8 weeks, we performed an in vivo steady state ¹³C-labled metabolite isotope infusion with our novel ¹³C labeled metabolite cocktail (3-hydroxybutyrate, glutamine, valine, lactate, glucose) and ¹³C labeled palmitate to quantify nutrient contribution to kidney and heart TCA cycle intermediates.

Results

At 4 weeks, mice develop CKD (hyperfiltration, elevated serum creatinine and urine albumin/creatinine ratio, moderate renal fibrosis) but with unchanged heart function or histology. At 8 weeks, mice progress to severe CKD (significantly decreased GFR, significantly increased serum creatinine and urine albumin/creatinine ratio, severe renal fibrosis) and have heart failure with preserved ejection fraction (increased serum markers, diastolic and strain parameters, cardiomyocyte hypertrophy). Preliminary data from our ¹³C-labled metabolite isotope infusions indicate nutrient contribution patterns to TCA cycle intermediates in CKD are similar in kidney and heart tissue.

Conclusion

We conclusively established a mouse model of HF secondary to CKD, in which mice first develop CKD at 4 weeks, then develop heart failure with preserved ejection fraction (HFpEF) by 8 weeks, phenocopying the human literature where CKD is an independent risk factor to HFpEF. Tracing studies indicate the heart and kidney have similar nutrient use in CKD, offering insights into targeted metabolic interventions for improved CKD and HF patient outcomes.

Funding

• Other U.S. Government Support