title: Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis.
abstract: Microvascular rarefaction, or loss of microvascular density, is increasingly implicated in the progression from acute ischemic kidney injury to chronic kidney disease. Microvascular dropout results in chronic tissue hypoxia, interstitial inflammation, and fibrosis. There is currently no therapeutic intervention for microvascular rarefaction. We hypothesize that capillary dropout begins with ischemic damage to endothelial mitochondria due to cardiolipin peroxidation, resulting in loss of cristae and the failure to regenerate ATP upon reperfusion. SS-31 is a cell-permeable peptide that targets the inner mitochondrial membrane and binds selectively to cardiolipin. It was recently shown to inhibit cardiolipin peroxidation by cytochrome c peroxidase activity, and it has been shown to protect mitochondrial cristae in proximal tubular cells during ischemia, and accelerated ATP recovery upon reperfusion. We found mitochondrial swelling and loss of cristae membranes in endothelial and medullary tubular epithelial cells after 45-min ischemia in the rat. The loss of cristae membranes limited the ability of these cells to regenerate ATP upon reperfusion and led to loss of vascular integrity and to tubular cell swelling. SS-31 prevented mitochondria swelling and protected cristae membranes in both endothelial and epithelial cells. By minimizing endothelial and epithelial cell injury, SS-31 prevented "no-reflow" after ischemia and significantly reduced the loss of peritubular capillaries and cortical arterioles, interstitial inflammation, and fibrosis at 4 wk after ischemia. These results suggest that mitochondria protection represents an upstream target for pharmacological intervention in microvascular rarefaction and fibrosis.
authors.affiliation: Dept. of Pharmacology, Weill Cornell Medical College, 1300 York Ave., New York, NY 10021. hhszeto@med.cornell.edu.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Soong
authors.forename: Surya V
authors.initials: SV
authors.lastname: Seshan
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004734:Energy Metabolism / Q000187:drug effects; D005355:Fibrosis; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D009393:Nephritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D002308:Cardiolipins; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000255:Adenosine Triphosphate
keywords: SS-31; Szeto-Schiller peptides; acute kidney injury; chronic kidney disease; mitochondrial cristae