A COMBINATION OF SIMVASTATIN AND A LOW-PROTEIN DIET INCREASES RENAL 2-OXOGLUTARATE DEHYDROGENASE ACTIVITY IN RATS.

Mitochondrial 2-oxoglutarate dehydrogenase complex (2-OGDH) that consists of multiple copies of 3 catalytic subunits (E1, E2, E3) is a regulatory enzyme of the tricarboxylic acid cycle. 2-OGDH together with branched-chain a-ketoacid dehydrogenase (BCKDH) and pyruvate dehydrogenase (PDH) belongs to the 2-oxoacid dehydrogenases family. It was shown that in protein-restricted rats simvastatin stimulated liver BCKDH, whereas it exerted no effect on BCKDH in rats fed a standard diet. We hypothesized that a combination of simvastatin and a low-protein diet could have an impact on renal 2-OGDH. The purpose of the study was to determine the effect of the combination of simvastatin and a low-protein diet on renal 2-OGDH in rats. Simvastatin (80 mg/kg b.wt/day) or the vehicle (0.3% methylcellulose) were administered orally (for 14 days) to rats fed a low-protein (8% protein) or standard (23% protein) diet. 2-OGDH activity, protein levels, and mRNA levels for E1 and E2 subunits were determined. In addition, serum creatinine level was measured. Results: The combination of simvastatin and a low-protein diet elicited an increase in renal 2-OGDH activity that corresponded to the increase of E1 protein, but not of E1 mRNA level. In contrast, simvastatin treatment did not affect 2-OGDH activity, nor protein and mRNA levels of E1 in rats fed a standard diet. Serum creatinine levels were not changed upon simvastatin administration in any group. In conclusion, the results of the present study indicate that the combination of simvastatin and a low-protein diet induces stimulation of the renal 2-OGDH complex probably at a post-transcriptional level. [ABSTRACT FROM AUTHOR]