Interaction of Hypoxia inducible factor 1α (HIF 1-α) and Perixosome proliferator-activated receptor α (PPAR-α) in the protection against ischemia reperfusion injury in the rat kidney.

Abstract

In response to reduced oxygen availability, cellular and molecular adaptive, cellular and molecular adaptive changes occur in living organisms. Interaction of hypoxia-inducible factor (HIF) and peroxisome proliferator-activated receptor (PPAR α) has been identified as an important mechanisms of cellular adaptation  to low oxygen. This study tested the hypothesis that inhibition of prolyl hydroxylase domain (PHD) through activation of PPAR α  confers protection against ischemia/reperfusion injury. In animals subjected to ischemia with or without PHD inhibitor  L-mimosine (L-MM) (600mg/kg).  Renal Blood Flow (RBF) recovered to 93± 8%, 56±7% (p< 0.001) and 87±10% (p< 0.001) in control, ischemic and L-mm treated groups respectively after 48hr of reperfusion. Coincident with these changes, serum nitric oxide decreased  by 33±3%  in  the ischemic group while L-MM treatment abolished the effect of ischemia (p<0.05). 24hr urine volume increased by 100 ±00% (p<0.001) and 3±0%  (p>0.05) in ischemic and L-MM treated groups respectively. Similarly, urinary protein excretion (24hr) increased 5-fold (p<0.001) in the  ischemic group but was attenuated to a 2-fold increase by L-MM (p< 0.05). However, when mice knock out of PPAR-α (-/-) where subjected to the same treatment, L-MM failed to exhibit any significant effect in any of the studied analytes. These findings suggest that stabilization of HIF-1α via inhibition of PHD through PPAR-α activation protects against Ischemia reperfusion injury (IRI) in the rat kidney.