期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 307, 期 1, 页码 F1-F11出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00067.2014
关键词
proximal tubule; ammoniagenesis; gluconeogenesis; pH-responsive; acid-base balance
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [DK37124, DK43704, DK75517]
- Austrian Science Fund (FWF) [P11126, P12705, P14981]
- Austrian Science Fund (FWF) [P14981, P11126, P12705] Funding Source: Austrian Science Fund (FWF)
Ammoniagenesis and gluconeogenesis are prominent metabolic features of the renal proximal convoluted tubule that contribute to maintenance of systemic acid-base homeostasis. Molecular analysis of the mechanisms that mediate the coordinate regulation of the two pathways required development of a cell line that recapitulates these features in vitro. By adapting porcine renal epithelial LLC-PK1 cells to essentially glucose-free medium, a gluconeogenic subline, termed LLC-PK1-FBPase(+) cells, was isolated. LLC-PK1-FBPase(+) cells grow in the absence of hexoses and pentoses and exhibit enhanced oxidative metabolism and increased levels of phosphate-dependent glutaminase. The cells also express significant levels of the key gluconeogenic enzymes, fructose-1,6-bisphosphatase (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK). Thus the altered phenotype of LLC-PK1-FBPase(+) cells is pleiotropic. Most importantly, when transferred to medium that mimics a pronounced metabolic acidosis (9 mM HCO3-, pH 6.9), the LLC-PK1-FBPase(+) cells exhibit a gradual increase in NH4+ ion production, accompanied by increases in glutaminase and cytosolic PEPCK mRNA levels and proteins. Therefore, the LLC-PK1-FBPase(+) cells retained in culture many of the metabolic pathways and pH-responsive adaptations characteristic of renal proximal tubules. The molecular mechanisms that mediate enhanced expression of the glutaminase and PEPCK in LLC-PK1-FBPase(+) cells have been extensively reviewed. The present review describes novel properties of this unique cell line and summarizes the molecular mechanisms that have been defined more recently using LLC-PK1-FBPase(+) cells to model the renal proximal tubule. It also identifies future studies that could be performed using these cells.
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