The renal response to alterations in systemic acid-base balance is complex and involves alterations in membrane transport and intracellular metabolic enzyme activities. One of these changes is an increase in the activity of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), which occurs as a result of increased gene transcription. The PEPCK gene, although expressed in other tissues, specifically responds to the acid-base state of the whole organism only in the kidney. The goal of this project is the elucidation of mechanisms by which the transcription of a specific gene (PEPCK) is rapidly stimulated in the kidney with metabolic acidosis. Since other genes may be uniquely expressed in kidney in response to metabolic acidosis, study of the properties of this gene as it interacts with the renal epithelial cell milieu may provide insights in the unique renal response as the major organ of external acid-base balance. Flanking areas of genomic DNA surrounding the PEPCK gene have already been shown to confer specificity of expression in response to hormones in renal cells. This study will proceed by using defined regions of the PEPCK gene and flanking DNA to modify the expression of heterologous genes expressed in transfected renal epithelial cell lines and to evaluate the pH responsive properties of this system. In addition, we will seek nuclear binding proteins which interact with the PEPCK gene and may mediate the pH response. The overall goal is a better understanding of the mechanisms of adaptation which accompany renal response to acid-base perturbations.
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