Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration

Abstract

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.

Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure

“…Indeed, a plethora of experimental data support the concept that such redox sensitive ‘stress proteins’ can exert dramatic renal protective effects (reviewed in ref. 8, 9). However, the most effective and safest way(s) of inducing these proteins in kidney remains to be defined.…”

“…We recently reported that administration of a sub-toxic dose of nitrited myoglobin (NMgb), in combination with Sn protoporphyrin, can safely and synergistically up-regulate potent cytoprotective proteins (e.g., HO-1, haptoglobin, IL-10) in mouse kidney (8). Thus, by 18 hrs post agent administration, striking protection against both ischemia-reperfusion and toxic (maleate, glycerol) ARF was induced.…”

“…Furthermore, these same cytoprotective genes were activated in extra-renal organs (most notably in liver). As a result, marked protection against ischemic and toxic hepatic injuries was expressed (8). The rationale for the above pharmacologic approach was as follows: 1) heme proteins, such as myoglobin, are potent inducers of redox sensitive cytoprotective genes (8-11); 2) nitrite binding to myoglobin Fe decreases its cytotoxic potential (8,12-15); 3) concomitant Sn protoporphyrin administration enhances nitrite-myoglobin signaling (8); and 4) SnPP can independently up-regulate HO-1 and haptoglobin expression, and synergize nitrited myoglobin-mediated cytoprotective gene induction (8,16).…”

“…Despite the observed efficacy and safety of the above approach (8), theoretical reservations might exist vis à vis the use of a potential nephrotoxin (myoglobin) as a renal cytoprotective agent. Furthermore, although SnPP has been safely administered to patients (e.g., to mitigate neonatal jaundice), no clinically available Sn protoporphyrin preparation exists.…”

Iron, hormesis, and protection in acute kidney injury

“…These investigators have previously shown that administration of nitrated myoglobin (heme protein) in combination with tin-protoporphyrin (HO-1 inducer) renders striking protection against AKI. 9 In the current study, Zager et al 8 replaced nitrated myoglobin with iron sucrose and showed that preadministration of iron sucrose combined with either tinprotoporphyrin or cyanocobalamin (also a protoporphyrin) induces renal protection in diverse models of AKI, whereas iron-sucrose alone was not effective. Furthermore, remote cardiac injury as measured by plasma troponin I levels was ameliorated.…”