The NRF2 stimulating agent, tin protoporphyrin, activates protective cytokine pathways in healthy human subjects and in patients with chronic kidney disease

BACKGROUND: Tin protoporphyrin (SnPP), a heme oxygenase 1 (HO‐1) inhibitor, triggers adaptive tissue responses that confer potent protection against acute renal‐ and extra‐renal tissue injuries. This effect is mediated, in part, via SnPP‐induced activation of the cytoprotective Nrf2 pathway. However, it remains unclear as to whether SnPP can also upregulate humoral cytokine defenses, either in healthy human subjects or in patients with CKD. If so, then systemically derived cytokines could contribute SnPP‐induced tissue protection. METHODS: SnPP (90 mg IV) was administered over 2 hr to six healthy human volunteers (HVs) and 12 subjects with stage 3–4 CKD. Plasma samples were obtained from baseline upto 72 hr post injection. Two representative anti‐inflammatory cytokines (IL‐10, TGFβ1), and a pro‐inflammatory cytokine (TNF‐α), were assayed. Because IL‐6 has been shown to induce tissue preconditioning, its plasma concentrations were also assessed. In complementary mouse experiments, SnPP effects on renal, splenic, and hepatic IL‐10, IL‐6, TGFβ1, and TNF‐α production (as gauged by their mRNAs) were tested. Tissue HO‐1 mRNA served as an Nrf2 activation marker. RESULTS: SnPP induced marked (~5–7x) increases in plasma IL‐10 and IL‐6 concentrations within 24–48 hr, and to equal degrees in HVs and CKD patients. SnPP modestly raised plasma TGFβ1 without impacting plasma TNF‐α levels. In mouse experiments, SnPP did not affect IL‐6, IL‐10, TNF‐α, or TGFβ1 mRNAs in kidney despite marked renal Nrf2 activation. Conversely, SnPP increased splenic IL‐10 and hepatic IL‐6/TGFβ1 mRNA levels, suggesting these organs as sites of extra‐renal cytokine generation. CONCLUSIONS: SnPP can trigger cytoprotective cytokine production, most likely in extra‐renal tissues. With ready glomerular cytokine filtration, extra‐renal/renal “organ cross talk” can result. Thus, humoral factors seemingly can contribute to SnPP’s cytoprotective effects.