Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies demonstrated that during cisplatin-induced acute renal failure, there is a significant reduction in proximal tubule fatty acid oxidation. We now report on the effects of peroxisome proliferator-activated receptor-alpha (PPAR alpha) ligand Wy-14643 (WY) on the abnormalities of medium chain fatty acid oxidation and pyruvate dehydrogenase complex (PDC) activity in kidney tissue of cisplatin-treated mice. Cisplatin causes a significant reduction in mRNA levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD). PPAR alpha ligand WY ameliorated cisplatin-induced acute renal failure and prevented cisplatin-induced reduction of mRNA levels and enzyme activity of MCAD. In contrast, in cisplatin-treated PPAR alpha null mice, WY did not protect kidney function and did not reverse cisplatin-induced decreased expression of MCAD. Cisplatin inhibited renal PDC activity before the development of acute tubular necrosis, and PDC inhibition was reversed by pretreatment with PPAR alpha agonist WY. Cisplatin also induced increased mRNA and protein levels of pyruvate dehydrogenase kinase-4 (PDK4), and PPAR alpha ligand WY prevented cisplatin-induced increased expression of PDK4 protein levels in wild-type mice. We conclude that PPAR alpha agonists have therapeutic potential for cisplatin-induced acute renal failure. Use of PPAR alpha ligands prevents acute tubular necrosis by ameliorating cisplatin-induced inhibition of two distinct metabolic processes, MCAD-mediated fatty acid oxidation and PDC activity.
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PMID:PPAR alpha ligand protects during cisplatin-induced acute renal failure by preventing inhibition of renal FAO and PDC activity. 1461 80

Renal proximal tubule cells from spontaneously hypertensive rats (SHR), compared with normotensive Wistar-Kyoto rats (WKY), have increased oxidative stress. The contribution of mitochondrial oxidative phosphorylation to the subsequent hypertensive phenotype remains unclear. We found that renal proximal tubule cells from SHR, relative to WKY, had significantly higher basal oxygen consumption rates, adenosine triphosphate synthesis-linked oxygen consumption rates, and maximum and reserve respiration. These bioenergetic parameters indicated increased mitochondrial function in renal proximal tubule cells from SHR compared with WKY. Pyruvate dehydrogenase complex activity was consistently higher in both renal proximal tubule cells and cortical homogenates from SHR than those from WKY. Treatment for 6 days with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, significantly increased renal pyruvate dehydrogenase complex activity and systolic blood pressure in 3-week-old WKY and SHR. Therefore, mitochondrial oxidative phosphorylation is higher in renal proximal tubule cells from SHR compared with WKY. Thus, the pyruvate dehydrogenase complex is a determinant of increased mitochondrial metabolism that could be a causal contributor to the hypertension in SHR.
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PMID:Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats. 2413 10