Tin protoporphyrin activates the oxidant-dependent NRF2-cytoprotective pathway and mitigates acute kidney injury

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Abstract

Tin protoporphyrin (SnPP), a heme oxygenase (HO) inhibitor, can paradoxically protect against diverse forms of acute kidney injury (AKI). This study sought potential underlying mechanisms. CD-1 mice received intravenous SnPP, followed 4–18 hours later by a variety of renal biochemical, histologic, and genomic assessments. Renal resistance to ischemic-reperfusion injury (IRI) was also sought. SnPP was rapidly taken up by kidney and was confined to proximal tubules. Transient suppression of renal heme synthesis (decreased δ aminolevulinic acid synthase expression), a 2.5-fold increase in “catalytic” Fe levels and oxidant stress resulted (decreased glutathione; increased malondialdehyde, and protein carbonyl content). Nrf2 nuclear translocation (˜2x Nrf2 increase; detected by enzyme-linked immunosorbent assay, Western blotting), with corresponding activation of ˜20 Nrf2-sensitive genes (RNA-Seq) were observed. By 18 hours after SnPP injection, marked protection against IRI emerged. This represented “preconditioning”, not a direct SnPP effect, given that SnPP administered at the time of IRI exerted no protective effect. The importance of transient oxidant stress in SnPP “preconditioning” was exemplified by the following: (1) oxidant stress induced by a different mechanism (myoglobin injection) recapitulated SnPP's protective action; (2) GSH treatment blunted SnPP's protective influence; (3) SnPP raised cytoprotective heavy chain ferritin (Fhc), a response enhanced by exogenous Fe injection; and (4) SnCl2, a ˜35- to 50-fold HO-1 inducer (not inhibitor) evoked neither oxidant stress nor mitigated IRI (seemingly excluding HO-1 activity in SnPP's protective effect). SnPP specifically accumulates within proximal tubule cells; transient “catalytic” Fe overload and oxidative stress result; Nrf2-cytoprotective pathways are upregulated; and these changes help protect against ischemic AKI.

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