Tin Protoporphyrin Activates the Oxidant Dependent NRF2 – Cytoprotective Pathway and Mitigates Acute Kidney Injury

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 186; pp. 1 - 18
• Main Authors: Johnson, Ali CM., BS, Delrow, Jeff J., PhD, Zager, Richard A., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017
• Subjects: Acute Kidney Injury - prevention & control; Animals; Ferric Compounds - administration & dosage; Ferric Compounds - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Glucaric Acid - administration & dosage; Glucaric Acid - pharmacology; Internal Medicine; 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; Fhc; IRI; ARF; FeS; HO; IR; BUN; SnPP; AKI
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2017.05.005

Abstract Tin protoporphyrin (SnPP), a heme oxygenase (HO) inhibitor, can paradoxically protect against diverse forms of AKI. This study sought potential underlying mechanisms. CD-1 mice received IV SnPP, followed 4-18 hrs 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 ELISA, Western blotting), with corresponding activation of ∼20 Nrf2-sensitive genes (RNA-Seq) were observed. By 18 hrs post-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: i) oxidant stress induced by a different mechanism (myoglobin injection) recapitulated SnPP’s protective action; ii) GSH treatment blunted SnPP’s protective influence; iii) SnPP raised cytoprotective heavy chain ferritin (Fhc), a response enhanced by exogenous Fe injection; and iv) SnCl2 , a ∼35-50 fold HO-1 inducer (not inhibitor) evoked neither oxidant stress nor mitigated IRI (seemingly excluding HO-1 activity in SnPP’s protective effect). Conclusions: 1) SnPP specifically accumulates within proximal tubule cells; transient “catalytic” Fe overload and oxidative stress result; Nrf2-cytoprotective pathways are up-regulated; and these changes help protect against ischemic AKI.