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A novel mitochondria‐targeted hydrogen sulfide delivery molecule prevents uraemia and diabetes‐induced renal cell oxidative stress
Author(s) -
Stevens Megan,
Payne Molly,
Innes Elayne,
Torregrossa Roberta of,
Wood Mark,
Stevens Maarten Koeners of,
Whiteman Matthew of,
Oltean Sebastian of
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.619.10
Subject(s) - oxidative stress , mitochondrion , reactive oxygen species , medicine , programmed cell death , population , kidney , diabetic nephropathy , kidney disease , transplantation , mitochondrial ros , pathophysiology , nephropathy , pharmacology , cancer research , chemistry , diabetes mellitus , endocrinology , microbiology and biotechnology , apoptosis , biology , biochemistry , environmental health
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 (H 2 S) deficiency, coinciding with mitochondrial dysfunction and increased oxidative stress. Mitochondria‐specific H 2 S‐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 H 2 S on mammalian cells appears to be overwhelmingly mitochondrial, the pathophysiological importance of mitochondrial H 2 S deficiency, and the potential therapeutic benefit of H 2 S 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 H 2 S 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 H 2 S 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 (Ser 453 ) 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 H 2 S 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 H 2 S deficiency could be a novel clinically applicable target for treatment in (chronic) kidney disease. Support or Funding Information British 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 .