The important metabolic function of gluconeogenesis is an exclusive property of kidney and liver. Renal gluconeogenesis has been characterized with respect to its substrates and physiological, hormonal and ionic modulators. It is evident that the major physiologic determinants of renal gluconeogenesis appear to act on the synthesis of the rate limiting enzyme on gluconeogenesis; phosphoenolpyruvate carboxykinase (PEPCK). It has become evident that PEPC synthesis is regulated at the level of nuclear transcription of PEPCK messenger RNA (mRNA). In addition to providing glucose, gluconeogenesis appears to be related to and pemissive for renal ammonaigenesis; a key process in the renal adaptation to an increased acid load. Although ammoniagenesis has been studied in the setting of the remnant kidney, there is little information on the adaptation of gluconeogenesis in the remnant kidney. We plan to impose a physiologic stimulus; acute metabolic acidosis, and to document a sequence of events culminating in renal gluconeogenesis; a physiologic response. This sequence of events; nuclear PEPCK mRNA transcription, increased cytoplasmic PEPCK mRNA, increased PEPCK enzymatic activity and finally, increased gluconeogenesis, forms a paradigm of the normal physiologic response. In applying these measurements to the model of progressive renal ablation, we will manipulate the major regulators of renal gluconeogenesis; dietary protein, and adrenal and the parthyroid status. The following methods will be used: 50-75%nephrectomy, adrenalectomy, parathyroidectomy, measurements of: nuclear PEPCK mRNA transcription and cytoplasmic mRNA levels, PEPCK activity and gluconeogenesis. Our results will address several questions: 1)-Is the gluconeogenic respone to an acid load altered in renal insufficiency, and if so is it in proportion to: a)-The degree of rnal insufficiency? b)-The degre of renal ammoniagenic response? 2)-Does dietary protein intake modify renal gluconeogenesis as it does ammoniagenesis? a)-If so, does it depend on hyperfiltration? 3)-Does adrenal hormone secretion condition the renal gluconeogenic response in normal and remnant kidneys? 4)-Is parathyroid hormone secretion premissive for renal gluconeogenesis in normal and remnant kidneys? 5)-Are altrations in renal gluconeogenic response a reflection of altered PEPCK mRNA synthesis at the nuclear level, at the level of PEPCK mRNA stability, at the expression of PEPCK activity or at another level of renal metabolism?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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University of California San Francisco
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