The phenomenon of so called renal “ischemic preconditioning”, whereby an initial ischemic insult induces resistance against subsequent kidney damage, has been well established in the experimental literature. However, a clinically applicable way to safely recapitulate this state has not been defined. We hypothesized that a unique combination of agents (nitrited myoglobin + Sn protoporphyrin) can achieve these ends by safely, and synergistically, increasing cytoprotective proteins (e.g., HO-1, IL-10, haptoglobin) in kidney cells. To test this hypothesis, CD-1 mice received 1 mg N-Mgb and 1 µmole SnPP, either alone or in combination. Renal cortical HO-1, haptoglobin, and IL-10 gene expression (mRNA, protein levels) were determined 4 and 18 hrs later. Cytoresistance to three forms of AKI were assessed (glycerol- induced rhabdomyolysis; maleate nephrotoxicity; post-ischemic AKI progression to CKD). To ascertain whether cytoresistance might emerge in extra-renal organs, hepatic HO-1, IL-10, and haptoglobin levels were also measured, and resistance to 25 min of hepatic ischemia-reperfusion injury and hepatotoxicity (intraperitoneal glycerol injection) was sought. N-Mgb + SnPP induced additive or synergistic increases in renal HO-1, haptoglobin, and IL-10 mRNA/protein levels (up to 20 fold) without inducing any apparent renal or extra-renal damage. By 18 hrs post treatment, marked, or complete, protection against glycerol-induced AKI, maleate- induced AKI, and post ischemic AKI progression to CKD had emerged. Combined N-Mgb+SnPP was more protective than was either agent alone (assessed in glycerol model). N-Mgb+SnPP also up-regulated cytoprotective pathways in liver, and induced marked protection against both hepatic ischemia-reperfusion and toxic liver damage. In sum, we posit that “preconditioning” with combined N-Mgb+SnPP administration represents a promising approach for protecting against diverse forms of renal and non renal (hepatic) forms of tissue damage.