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

Transl Res. 2017 Aug:186:1-18. doi: 10.1016/j.trsl.2017.05.005. Epub 2017 May 19.

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.

MeSH terms

  • Acute Kidney Injury / prevention & control*
  • Animals
  • Ferric Compounds / administration & dosage
  • Ferric Compounds / pharmacology*
  • Ferric Oxide, Saccharated
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glucaric Acid / administration & dosage
  • Glucaric Acid / pharmacology*
  • Male
  • Metalloporphyrins / administration & dosage
  • Metalloporphyrins / pharmacology*
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidants
  • Protein Binding
  • Protoporphyrins / administration & dosage
  • Protoporphyrins / pharmacology*
  • Reperfusion Injury

Substances

  • Ferric Compounds
  • Metalloporphyrins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Oxidants
  • Protoporphyrins
  • tin protoporphyrin IX
  • Ferric Oxide, Saccharated
  • Glucaric Acid