Advisory Committee Chair
Christian Faul
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Chronic kidney disease (CKD) is characterized as irreversible progressive loss of renal function and affects over one tenth of the global population. Although CKD-associated comorbidities contribute significantly to its mortality, the lungs are often not considered. Lung diseases make up three of the top six leading causes of death worldwide and share many comorbidities with CKD. Clinical reports show that CKD patients are more likely to develop obstructive and restrictive lung diseases, but the mechanisms underlying this propensity for CKD-associated pulmonary complications are unknown. Hyperphosphatemia and associated elevations of fibroblast growth factor (FGF) 23, two of many consequences of reduced renal function, have been attributed to inflammation and injury in the kidney, heart, and liver and may be a key link in underlying kidney-lung crosstalk. Employing hyperphosphatemic mouse models, in the presence and absence of accompanying CKD, we characterize lung inflammation, altered bronchial epithelial histology, and exacerbations of fibrotic lung injury. Our in vitro studies show similar proinflammatory responses to elevated phosphate in human bronchial epithelial cells (HBEC) and human lung fibroblasts. Phosphate-induced upregulation of proinflammatory cytokines in HBECs is further exacerbated by exposure to cigarette smoke (CS), which is a common cause of COPD. Co-treatment of FGF23 with phosphate or phosphate and CS attenuated the proinflammatory responses in HBECs, independent of extracellular signal-regulated kinase (ERK) signaling alterations. In addition to phosphate-induced ERK activation, fibroblasts also exhibited protein kinase B (PKB/AKT) phosphorylation that accompanied upregulation of proinflammatory cytokines. Inhibition of sodium-phosphate cotransporters or FGF receptor (FGFR) 1 decreased ERK and AKT activation and the accompanying proinflammatory response. These data establish novel pathways that may link kidney-lung disease crosstalk experienced during CKD-associated hyperphosphatemia. By highlighting phosphate homeostasis as a link between renal function decline and lung injury, we aim to bring attention to the importance of lung assessment in the management of CKD patients. Further understanding of the biological pathways underlying kidney-lung crosstalk could ultimately lead to novel therapeutics targeting the hyperphosphatemic effects of CKD in extrarenal organs that improve overall survival and reduce the risk of pulmonary comorbidities in patients with renal dysfunction.
Recommended Citation
Bollenbecker, Seth, "Phosphate Drives Pulmonary Inflammation Through Fgfr1, Erk, And Akt Signaling" (2024). All ETDs from UAB. 3854.
https://digitalcommons.library.uab.edu/etd-collection/3854
