Hypoxia in the tubulointerstitium has been thought to play pivotal roles in the pathophysiology of
acute renal failure and the progression of
chronic kidney disease. Pre-induction of
hypoxia-inducible and renoprotective gene expression may protect subsequent ischemic injury. This study evaluated the efficacy of
cobalt, which inhibits HIF-1 degradation and increases the expression level of
hypoxia-related genes, in an acute ischemic tubulointerstitial injury model of rats. Ischemic renal injury was induced by 45-min clamping of renal pedicles with contralateral
nephrectomy. Elevation of serum
creatinine and morphologic injury after the ischemic insult was observed. Administration of
cobalt chloride afforded striking functional improvement (mean +/- SEM
creatinine in mg/dl: Co treatment group, 2.14 +/- 1.21; control, 3.69 +/- 1.43; P < 0.05) associated with amelioration of tubulointerstitial damage.
Cobalt treatment also reduced macrophage infiltration significantly. In the kidney of rats treated with
cobalt,
mRNA levels of several genes that serve for tissue protection, such as HO-1, EPO, Glut-1, and
VEGF, were increased before ischemic injury. Upregulation of HO-1 by
cobalt was confirmed at the
protein level.
Subcutaneous injection of
cobalt also ameliorated ischemic injury, which was associated with upregulation of renal HIF-1alpha
protein expression. These results suggest that protection against hypoxic tubulointerstitial injury by
cobalt administration is mediated by induction of renoprotective gene expression. HIF induction is one possible and attractive explanation for the observed effects.