Acute kidney injury (AKI) induces adaptive responses within proximal tubular cells which serve to protect them from further ischemic or toxic damage. However, it is not known whether uremia, a potential consequence of AKI, independently alters tubular injury susceptibility. To address this issue, CD-1 mice were subjected to bilateral ureteral transection (BUTx), which produces uremia (BUNs ~150 mg/dL) in the absence of direct renal damage. Proximal tubular segments were then isolated from BUTx and control mice and subjected to in vitro hypoxic injury. Additionally, 'in vitro uremia' was modeled in isolated tubules or in cultured proximal tubule (HK-2) cells by adding either: i) peritoneal dialysate (obtained from mice with bilateral ureteral obstruction); ii) peritoneal fluid (from BUTx mice); or iii) normal human urine (pH 7.4; ± boiling). Effects on injury severity (LDH release) were assessed. Finally, because uremia is a pro-oxidant state, it was hypothesized that BUTx would increase renal lipid peroxidation (malondialdehyde, MDA) and induce heme oxygenase -1 (HO-1), a redox sensitive cytoprotective protein. BUTx conferred striking protection against hypoxic damage. This could be partially modeled in tubules and HK-2 cells by inducing 'in vitro uremia'. Urine's protective action was heat labile (largely destroyed by boiling). BUTx caused a tripling of both renal MDA and HO-1 protein levels. Increased HO-1 transcription was likely involved, based on a tripling of both HO-1 mRNA and RNA polymerase II binding along the HO-1 gene (ChIP assay). 'Gene activating' histone modifications (H3K4m3; H2A.Z) at HO-1 loci were also observed. Conclusions: Uremia, per se, can contribute to the AKI- induced cytoresistance. Both low molecular weight, heat labile, cytoprotective factor(s), and uremia- induced renal stress responses (e.g.,HO-1 gene activation) are likely involved. Finally, renal HO-1 induction following AKI may reflect both direct cell injury effects and adaptations to uremia.