Clayton BradyMD/PhD program (G4)University at BuffaloPI - Dr. Mark Parker
Title: Investigating the role of NBCe1-B in renal and cardiac function
Introduction: Metabolic acidosis (MAc) is associated with both the progression of chronic kidney disease and the development of heart failure. The electrogenic sodium-bicarbonate co-transporter, NBCe1-B, is expressed in both the kidney and the heart and is suggested to contribute to the physiologic/pathophysiologic responses of these organs to MAc. Therefore, we aimed to clarify the role of NBCe1-B in the kidney and the heart.
Methods: To investigate the role of NBCe1-B in the kidney, wild-type (WT) and NBCe1-B knockout (KO) mice were subjected to control or MAc-challenged (induced via 0.28M NH4Cl) conditions for 1-3 days while housed in metabolic cages. After which, blood-gas/electrolytes were obtained via cardiac puncture, kidneys were excised for immunohistochemistry or western blot, and urinary acid-excretion was assessed in 24-hour urine samples. To investigate the role of NBCe1-B in the heart, ECG and echocardiography assessments were made in WT and KO mice, followed by heart excision and analysis via histology, western blot, and RNA-seq.
Results: Rather than negatively affecting kidney ammonia excretion, loss of NBCe1-B led to elevated ammonia excretion in male mice. We propose that loss of NBCe1-B in a chemosensitive region of the brainstem leads to inappropriately elevated CO2 levels, which stimulates renal ammonia excretion. In the heart, loss of NBCe1-B led to a significant reduction in ejection fraction and fractional shortening, which along with histological analysis indicates a dilated cardiomyopathy-like phenotype. We further observed prolonged QT intervals in KO mice. Together with results of western blot and RNA-seq, this suggests a mechanism of heart failure centered on the Ca2+ activated calcineurin-Mef2 pathway.
Conclusion: Overall, the response of KO mice to MAc alongside their baseline cardiac abnormalities, implicates NBCe1-B in the pathophysiologic response underlying MAc-induced cardio-renal dysfunction.