Abstract: FR-PO290
Restoration of Branched-Chain Amino Acid Catabolism Improves Kidney Function in Preclinical CKD Models
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Roth Flach, Rachel, Pfizer Inc, New York, New York, United States
- Bollinger, Eliza, Pfizer Inc, New York, New York, United States
- Williams, George Edward, Pfizer Inc, New York, New York, United States
- Piper, Mary, Pfizer Inc, New York, New York, United States
- Steen, Kimberly L., Pfizer Inc, New York, New York, United States
- Neale, Kelly Tam, Pfizer Inc, New York, New York, United States
- Chen, Xian, Pfizer Inc, New York, New York, United States
- Marshall, Mackenzie E., Pfizer Inc, New York, New York, United States
- Jagarlapudi, Srinath, Pfizer Inc, New York, New York, United States
- Zhang, Ying, Pfizer Inc, New York, New York, United States
- Kuang, Elaine, Pfizer Inc, New York, New York, United States
- Callahan, Daniel, Pfizer Inc, New York, New York, United States
- Stansfield, John, Pfizer Inc, New York, New York, United States
- Daurio, Natalie A., Pfizer Inc, New York, New York, United States
- Crane, Justin, Pfizer Inc, New York, New York, United States
- Hirenallur-Shanthappa, Dinesh K., Pfizer Inc, New York, New York, United States
- Groarke, John D., Pfizer Inc, New York, New York, United States
- Zhang, Bei Betty, Pfizer Inc, New York, New York, United States
Background
Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs are elevated in HF patient myocardium. The rate limiting step of BCAA catabolism is decarboxylation by branched chain ketoacid dehydrogenase enzyme (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically. BDK inhibitors such as BT2 have been used preclinically and have demonstrated improvements in cardiometabolic outcomes, but the role of BDK inhibition in renal dysfunction has not been evaluated.
Methods
The BDK inhibitor BT2 was used in the ZSF1 (cross between Zucker diabetic ZDF rat and spontaneously hypertensive SHHF rat) rat model and SDT (spontaneously diabetic torii) rat model with uninephrectomy to test the impact of BDK inhibition on CKM parameters including urine output, albuminuria, GFR, and histology.
Results
BCAA catabolic impairment is associated with and may be causal to CKM, as treatment with the BDK inhibitor BT2 improved urine protein content, glomerular filtration rate, kidney hypertrophy, and kidney pathology in CKM models. Coadministration of BT2 and empagliflozin restored renal function and gene expression signatures towards that of healthy rats.
Conclusion
These data suggest that BDK inhibition could represent a therapeutic avenue for CKM.
Funding
- Commercial Support – Pfizer Inc