CHRONIC KIDNEY DISEASE LEADS TO HYPOXIA INDUCIBLE FACTOR-1ALPHA TO HYPOXIA INDUCIBLE FACTOR-2ALPHA SWITCH IN THE GASTROCNEMIUS MUSCLE

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-1 alpha and-2 alpha 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-1 alpha increased in MG and ML for CKD1/2 versus CON. HIF-1 alpha decreased in MG and increased in ML for CKD5/6 versus CON and CKD1/2. HIF-2 alpha increased in MG for CKD5/6 and CKD1/2 versus CON. HIF-2 alpha 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 mu M), MCP-1 (609 +/- 255; 489 +/- 265 versus 292 +/- 113 pg/ml), respectively. CKD had a different effect on protein expression patterns of HIF-1 alpha ,-2 alpha and PHDs depending on muscle type. A HIF-1 alpha to HIF-2 alpha switch in glycolytic MG in CKD5/6 might be a protective mechanism against tissue hypoxia and oxidative stress.