12595275

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6

The present study hypothesized that superoxide (O2(-)*) importantly contributes to the regulation of hypoxia-inducible factor (HIF)-1alpha expression at posttranscriptional levels in renal medullary interstitial cells (RMICs) of rats. By Western blot analysis, it was found that incubation of RMICs with O2(-)* generators xanthine/xanthine oxidase and menadione significantly inhibited the hypoxia- or CoCl(2)-induced increase in HIF-1alpha levels and completely blocked the increase in HIF-1alpha levels induced by ubiquitin-proteasome inhibition with CBZ-LLL in the nuclear extracts from these cells. Under normoxic conditions, a cell-permeable O2(-)* dismutase (SOD) mimetic, 4-hydroxyl-tetramethylpiperidin-oxyl (TEMPOL) and PEG-SOD, significantly increased HIF-1alpha levels in RMICs. Two mechanistically different inhibitors of NAD(P)H oxidase, diphenyleneiodonium and apocynin, were also found to increase HIF-1alpha levels in these renal cells. Moreover, introduction of an anti-sense oligodeoxynucleotide specific to NAD(P)H oxidase subunit, p22(phox), into RMICs markedly increased HIF-1alpha levels. In contrast, the OH* scavenger tetramethylthiourea had no effect on the accumulation of HIF-1alpha in these renal cells. By Northern blot analysis, scavenging or dismutation of O2(-)* by TEMPOL and PEG-SOD was found to increase the mRNA levels of an HIF-1alpha-targeted gene, heme oxygenase-1. These results indicate that increased intracellular O2(-)* levels induce HIF-1alpha degradation independently of H(2)O(2) and OH* radicals in RMICs. NAD(P)H oxidase activity may importantly contribute to this posttranscriptional regulation of HIF-1alpha in these cells under physiological conditions.

eng

IM

MEDLINE

1931-857X

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NLM

F1207-15

pubmed-meshheading:12595275-Animals, pubmed-meshheading:12595275-Blotting, Northern, pubmed-meshheading:12595275-Blotting, Western, pubmed-meshheading:12595275-Cell Hypoxia, pubmed-meshheading:12595275-Cell Nucleus, pubmed-meshheading:12595275-Cell Separation, pubmed-meshheading:12595275-Cobalt, pubmed-meshheading:12595275-DNA, Complementary, pubmed-meshheading:12595275-Free Radical Scavengers, pubmed-meshheading:12595275-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:12595275-Kidney Medulla, pubmed-meshheading:12595275-Leupeptins, pubmed-meshheading:12595275-Male, pubmed-meshheading:12595275-NADPH Oxidase, pubmed-meshheading:12595275-Oligodeoxyribonucleotides, Antisense, pubmed-meshheading:12595275-Oxidation-Reduction, pubmed-meshheading:12595275-Rats, pubmed-meshheading:12595275-Rats, Wistar, pubmed-meshheading:12595275-Reactive Oxygen Species, pubmed-meshheading:12595275-Transcription Factors, pubmed-meshheading:12595275-Transcriptional Activation, pubmed-meshheading:12595275-Vitamin K 3, pubmed-meshheading:12595275-Xanthine Oxidase

Redox regulation of HIF-1alpha levels and HO-1 expression in renal medullary interstitial cells.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't