Chronic kidney disease leads to hypoxia inducible factor-1alpha to hypoxia inducible factor-2alpha switch in the gastrocnemius muscle.

Abstract

Hipoxia inducible factor-1 and HIF-2 are responsible for the adaptation of cell metabolism to hypoxia. Previously, a more severe capillary rarefaction was found in locomotor than in postural muscles of uremic animals. The aim of this study was to analyze the expression patterns of HIF and prolyl hydroxylases (PHDs) in functionally different skeletal muscles in uremic rats, an experimental model of chronic kidney disease (CKD). Rats were randomized to sham operation - CON, uninephrectomy - CKD1/2 or subtotal nephrectomy - CKD5/6. After 4 weeks, expression of HIF-1α and -2α and PHD proteins was measured using WB in locomotor, gastrocnemius muscle (MG) and postural, longissimus thoracis muscle (ML). Serum concentrations of creatinine (Cr), hemoglobin (Hb), haptoglobin (Hp), MCP-1, AGEs, homocysteine (Hcy) were measured. HIF-1α increased in MG and ML for CKD1/2 versus CON. HIF-1α decreased in MG and increased in ML for CKD5/6 versus CON and CKD1/2. HIF-2α increased in MG for CKD5/6 and CKD1/2 versus CON. HIF-2α was not detected in ML in any group. PHD1 was not detected in MG in any group. PHD1 in ML was not detected in CON, but increased in CKD5/6 and CKD1/2. PHD2 decreased in MG but increased in ML for CKD5/6 versus CKD1/2 and CON. PHD3 did not differ between groups in MG, but in ML decreased in CKD5/6 versus CON and CKD1/2. There were significant differences for CKD5/6 and CKD1/2 versus CON in: Cr (1.2 ± 0.2; 0.7 ± 0.1 versus 0.8 ± 0.3 mg/dl), Hb (11.4 ± 3.1; 13.7 ± 0.7 versus 14.1 ± 1 g/dl), Hp (1.6 ± 0.6; 1.6 ± 0.6 versus 0.7 ± 0.4 mg/ml), AGEs (5.1 ± 0.6; 4.3 ± 1.2 versus 4.6 ± 0.9 AU), Hcy (7.2 ± 1.2; 5.1 ± 0.5 versus 4.9 ± 0.5 μM), MCP-1 (609 ± 255; 489 ± 265 versus 292 ± 113 pg/ml), respectively. CKD had a different effect on protein expression patterns of HIF-1α, -2α and PHDs depending on muscle type. A HIF-1α to HIF-2α switch in glycolytic MG in CKD5/6 might be a protective mechanism against tissue hypoxia and oxidative stress.

• Authors: M Flisinski, E Wisniewska-Chudy, A Brymora, A Stefanska, P Strozecki, J Manitius
• Journal: Journal of physiology and pharmacology : an official journal of the Polish Physiological Society (J Physiol Pharmacol) Vol. 68 Issue 3 Pg. 419-425 (Jun 2017) ISSN: 1899-1505 [Electronic] Poland
• PMID: 28820398 (Publication Type: Journal Article)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hif1a protein, rat
• Homeodomain Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• endothelial PAS domain-containing protein 1

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Homeodomain Proteins (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Muscle, Skeletal (metabolism)
• Rats, Wistar
• Renal Insufficiency, Chronic (metabolism)