title: A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis.
abstract: Revascularization improves blood pressure but not renal function in most patients with atherosclerotic renal artery stenosis (ARAS), possibly related to injury incurred during renal reperfusion. Bendavia, a novel tetrapeptide that inhibits mitochondrial permeability transition pore opening, reduces apoptosis, oxidative stress, and ischemia-reperfusion injury in experimental models. However, its potential for improving renal response to revascularization of chronic ARAS is unknown. We hypothesized that adjunct Bendavia would improve renal structure and function after percutaneous transluminal renal angioplasty (PTRA). Pigs were treated after 6 weeks of ARAS or control with PTRA+stenting (or sham), adjunct continuous 4-hour infusion of Bendavia (0.05 mg/kg IV) or vehicle (n=7 each) during PTRA. Single-kidney renal blood flow and glomerular filtration rate were studied 4 weeks later and renal mitochondrial biogenesis, microvascular architecture, and injurious pathways evaluated ex vivo. Monocyte chemoattractant protein-1 levels rose after PTRA, suggesting inflammatory injury. Bendavia did not immediately affect inflammatory cytokine levels, yet 4 weeks later, stenotic kidney renal blood flow and glomerular filtration rate both improved (44.00 ± 0.21% and 36.40 ± 10.21%, respectively) in ARAS+PTRA+Bendavia compared with ARAS+PTRA+vehicle. Renal mitochondrial biogenesis was restored after PTRA+Bendavia, and microvascular rarefaction, apoptosis, oxidative stress, tubular injury, and fibrosis decreased. Infusion of Bendavia during PTRA preserved mitochondrial biogenesis, renal hemodynamics, and function, and attenuated tissue injury in swine ARAS. Thus, functional mitochondrial injury during renal reperfusion may sustain renal inflammatory injury and limit kidney recovery after PTRA. Potent antiapoptotic and antioxidant effects provide Bendavia a novel therapeutic potential for improving kidney outcomes after PTRA in experimental ARAS.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Eirin
authors.forename: Zilun
authors.initials: Z
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: James D
authors.initials: JD
authors.lastname: Krier
authors.forename: John R
authors.initials: JR
authors.lastname: Woollard
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhu
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Herrmann
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Textor
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
mesh_terms: D017130:Angioplasty; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000378:metabolism / Q000628:therapy*; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D012078:Renal Artery Obstruction / Q000378:metabolism / Q000628:therapy*; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D018932:Chemokine CCL2; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide