Back to Search
Start Over
Preconditional Activation of Hypoxia-Inducible Factors Ameliorates Ischemic Acute Renal Failure
- Source :
- Journal of the American Society of Nephrology. 17:1970-1978
- Publication Year :
- 2006
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2006.
-
Abstract
- Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Normoxic degradation of HIF is mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative alpha-subunits by HIF prolyl hydroxylases (PHD). It was hypothesized that inhibition of HIF degradation by either hypoxia or pharmacologic inhibition of PHD would confer protection against subsequent ischemic injury. For testing this hypothesis ischemic acute renal failure was induced in rats by 40 min of clamping of the left renal artery after right-sided nephrectomy. Before surgery, pretreatment with either carbon monoxide, leading to tissue hypoxia, or the novel PHD inhibitor FG-4487 was applied. No toxic effects of FG-4487 were observed. Both pretreatments strongly induced the accumulation of HIF-1alpha and HIF-2alpha in tubular and peritubular cells, respectively, as well as HIF target gene expression. The course of subsequent ischemic injury was significantly ameliorated by both strategies of preconditioning, as evident from a significant improvement of serum creatinine and serum urea after 24 and 72 h. Furthermore, tissue injury and apoptosis were less severe, which were quantified by application of a standardized histologic scoring system in a blinded manner. In conclusion, the data provide proof of principle that preconditional activation of the HIF system protects against ischemic injury. Inhibiting the activity of HIF hydroxylases therefore seems to have considerable clinical perspectives.
- Subjects :
- Male
Nephrology
medicine.medical_specialty
Premedication
Procollagen-Proline Dioxygenase
Apoptosis
Cell Line
Rats, Sprague-Dawley
Hydroxylation
chemistry.chemical_compound
Internal medicine
Animals
Urea
Medicine
Hypoxia
Transcription factor
Carbon Monoxide
Creatinine
Renal ischemia
business.industry
Macrophages
General Medicine
Acute Kidney Injury
Hypoxia (medical)
Hypoxia-Inducible Factor 1, alpha Subunit
Rats
Endocrinology
Gene Expression Regulation
chemistry
Hypoxia-inducible factors
Reperfusion Injury
Hypoxia-Inducible Factor 1
medicine.symptom
business
Subjects
Details
- ISSN :
- 10466673
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology
- Accession number :
- edsair.doi.dedup.....f6cbb8937a4ab19382e6bd161cc81e46