Glomerular inflammation induces resistance to tubular injury in the rat. A novel form of acquired, heme oxygenase-dependent resistance to renal injury

Considerable attention is directed to a surprising biologic phenomenon wherein tissues exposed to one insult acquire resistance to another. We identify a novel example of acquired resistance to acute renal failure and a mechanism that contributes to such resistance. Nephrotoxic serum, administered to rats 24 h before the induction of glycerol-induced acute renal failure, reduces functional and structural injury that occurs in this model. Since heme oxygenase, the rate-limiting enzyme in heme degradation, protects against heme protein-induced renal injury, we questioned whether induction of heme oxygenase underlies the protection afforded by nephrotoxic serum. Kidney heme oxygenase (HO-1) mRNA was induced 6 h after nephrotoxic serum and renal tubules were identified as the site of expression of heme oxygenase protein. Induction of heme oxygenase was accompanied by increased renal content of ferritin but not by induction of other antioxidant enzymes. Inhibition of heme oxygenase prevented the protection afforded by nephrotoxic serum. Nephrotoxic serum did not protect against ischemic acute renal failure, a model in which heme oxygenase is not induced. Thus, nephrotoxic serum protects against glycerol-induced acute renal failure by inducing heme oxygenase in tubules. This study provides the first demonstration of resistance to tubular injury acquired from glomerular inflammation, uncovers a mechanism for such resistance, and exposes the dialogue that occurs between glomeruli and tubules.