Pilot--Regulation of Renal Pyruvate Dehydrogenase During Acidosis

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

The objective of this work is to establish the importance of regulation of the pyruvate dehydrogenase (PDH) complex in the kidney in maintenance of acid-base balance. Activity of the pyruvate dehydrogenase complex is regulated by covalent modification. Phosphorylation and inactivation of the complex is catalyzed by four pyruvate dehydrogenase kinase (PDK) isoenzymes; dephosphorylation by two pyruvate dehydrogenase phosphatase (PDP) isoenzymes. Unique regulatory properties of these isoenzymes and differences in their levels of expression in different cell types provide tissue specific control of the activity of the pyruvate dehydrogenase complex. The basis for this proposed work is our preliminary data indicating that two of the PDK isoenzymes, PDK2 and PDK4, are increased in the kidney by metabolic acidosis. We propose therefore that increased expression of these PDKs results in inactivation of pyruvate dehydrogenase complex, which promotes generation of new bicarbonate by the kidney. Our working hypothesis is that alterations in the expression of the PDK2 and PDK4 isoenzymes cause hyperphosphorylation and therefore inactivation of pyruvate dehydrogenase complex in kidney during metabolic acidosis. The hypothesis will be tested by: (a) determining the effects of acute and chronic metabolic acidosis and alkalosis on activity state of the PDH complex and the expression levels of its kinases and phosphatases in rat kidney; (b) determining whether the compensatory mechanism for metabolic acidosis is abnormal in the kidney of the PDK4 null mouse; and (c) establish factors and mechanisms that regulate expression of PDK2, PDK4, and PDP2 in the kidney. The findings are expected to provide new insight with respect to an important compensatory mechanism for life threatening metabolic acidosis.