A novel mitochondria‐targeted hydrogen sulfide delivery molecule prevents uraemia and diabetes‐induced renal cell oxidative stress

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Chronic Kidney Disease (CKD) is a disturbingly fast growing global public health problem affecting an estimated 9–16% of the world population. We and others have confirmed that cardiovascular disease is often a state of hydrogen sulfide (H2S) deficiency, coinciding with mitochondrial dysfunction and increased oxidative stress. Mitochondria‐specific H2S‐delivery molecules such as AP39 have been shown to protect the kidney during ischaemia‐reperfusion injury and during organ transplantation. Although the primary effect of endogenous and pharmacological H2S on mammalian cells appears to be overwhelmingly mitochondrial, the pathophysiological importance of mitochondrial H2S deficiency, and the potential therapeutic benefit of H2S in CKD models of uremic stress and diabetic nephropathy have not yet been explored.To elucidate the pathophysiology of CKD‐induced uremic stress, we first investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on the production of reactive oxygen species (‘ROS’) in multiple immortalised glomerular cell lines (glomerular endothelial cell [GEnCs], podocytes [PODs], and proximal tubule epithelial cells [PTECs]). Furthermore, we investigated the effects of mitochondria‐targeted H2S delivery molecules on IS‐induced ‘ROS’ production. Preliminary data showed that IS increased ‘ROS’ production in PODs and PTECs (100 μg/ml; P<0.05) and that the mitochondria‐targeted H2S delivery molecule AP39 (100nM) at least partially prevented this. We also investigated the effect of IS treatment on cell death, and whether AP39 was able to prevent this. IS (100ug/ml) induced significant cell death after 24 hrs treatment in both GEnCs and PODs, which was prevented by treatment with AP39 (100nM) (P<0.05). In addition to this, we found that AP39 increased the phosphorylation (Ser453) of the cytoprotective AKT in GEnCs exposed to diabetic and uremic stress. AP39 also prevented the mitochondria‐cytoplasmic translocation of the pro‐apoptotic factor cytochrome c in diabetic and uremic‐stressed GEnCs (P<0.05).These preliminary data indicate that uremic states may deteriorate renal function via mitochondrial dependent oxidative stress, which could be prevented by therapeutic H2S delivery. Indeed, the mitochondrial ROS generation, cell death, and cytochrome c release into the cytoplasm by uremic toxins and a diabetic environment in renal cells were, at least in part, reversed by AP39. Further studies are currently underway to determine whether mitochondrial H2S deficiency could be a novel clinically applicable target for treatment in (chronic) kidney disease.Support or Funding InformationBritish Heart Foundation and MRC funded research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.