d-arg-dmt-lys-phe-nh2 and Renal-Artery-Obstruction

Atherosclerotic renal artery stenosis reduces renal blood flow (RBF) and amplifies stenotic kidney hypoxia. Revascularization with percutaneous transluminal renal angioplasty (PTRA) and stenting often fails to recover renal function, possibly because of ischemia/reperfusion injury developing after PTRA. Elamipretide is a mitochondrial-targeted peptide that binds to cardiolipin and stabilizes mitochondrial function. We tested the hypothesis that elamipretide plus PTRA would improve renal function, oxygenation, and RBF in patients with atherosclerotic renal artery stenosis undergoing PTRA.. Adjunctive elamipretide during PTRA was associated with attenuated postprocedural hypoxia, increased RBF, and improved kidney function in this pilot trial. These data support a role for targeted mitochondrial protection to minimize procedure-associated ischemic injury and to improve outcomes of revascularization for human atherosclerotic renal artery stenosis.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01755858.

Topics: Aged; Angioplasty, Balloon; Antioxidants; Atherosclerosis; Computed Tomography Angiography; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypoxia; Infusions, Intravenous; Kidney; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondria; Multidetector Computed Tomography; Oligopeptides; Oxidative Stress; Perfusion Imaging; Pilot Projects; Recovery of Function; Renal Artery Obstruction; Renal Circulation; Reperfusion Injury; Risk Factors; Stents; Time Factors; Treatment Outcome

Atherosclerotic renal artery stenosis (ARAS) may cause kidney injury and mitochondrial dysfunction, which is linked to cellular senescence. Elamipretide, a mitochondria-targeted peptide, improves renal function in ARAS, but whether it alleviates senescence is unknown. We hypothesized that elamipretide would reduce senescence stenotic kidney (STK) in ARAS.. Domestic pigs were randomized to control and unilateral ARAS untreated or treated with subcutaneous elamipretide (5d/wk) for 4 weeks starting after 6 weeks of ARAS or sham (n=6 each). After completion of treatment, STK renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in-vivo using multi-detector computed-tomography. Renal fibrosis and oxidative stress were analyzed in trichrome- and dihydroethidium-stained slides, respectively. Mitochondrial markers involved in the electrontransport chain (COX4, ATP/ADP ratio), biogenesis (PGC1α, PPARα), dynamics (MFN2, DRP1), and mitophagy (parkin, p62) were measured in the kidney using ELISA, western-blot, and immunohistochemistry. Cellular senescence (senescence-associated β-galactosidase and heterochromatin foci, phosphorylated-H2AX, and p16/21/53) and senescence-associated secretory phenotype (SASP; PAI-1, MCP-1, TGFβ, and TNFα) markers were studied by microscopy, quantitative reverse transcription-polymerase chain reaction, and western-blot.. Blood pressure was elevated whereas STK-RBF and GFR were decreased in ARAS pigs, and tissue scarring was increased. ARAS induced STK cellular senescence and accumulated dysfunctional mitochondria, which were associated with cardiolipin loss, upregulated mitochondrial biogenesis, and defective mitophagy. Elamipretide normalized STK-RBF and GFR, alleviated fibrosis and oxidative stress, and restored mitochondrial cardiolipin, biogenesis, and mitophagy in ARAS, but did not change SASP markers, and attenuated only senescenceassociated β-galactosidase activity and p53 gene expression.. Mitochondrial protection improved renal function and fibrosis in the ARAS STK, but only partly mitigated cellular senescence. This finding suggests that mitochondrial dysfunction may not be a major determinant of cellular senescence in the early stage of ARAS.

Topics: Animals; Cardiolipins; Cellular Senescence; Creatinine; Diet, High-Fat; Disease Models, Animal; Female; Fibrosis; Glomerular Filtration Rate; Kidney; Mitochondria; Mitophagy; Oligopeptides; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Renal Artery Obstruction; Renal Circulation; Swine; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Topics: Humans; Oligopeptides; Percutaneous Coronary Intervention; Protective Agents; Renal Artery Obstruction; Reperfusion Injury; ST Elevation Myocardial Infarction; Stents

Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH-induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury.. After 12 weeks of hypercholesterolemic (HC)-RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial-targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner-membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector-computed tomography and oxygenation by blood-oxygen-level-dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic-reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert-butyl hydroperoxide (tBHP) untreated or treated with MTP. Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin-sensitive sarcoplasmic reticulum Ca(2+)-ATPase activity that declined in HC-RVH normalized in MTP-treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP-treated pigs. In tBHP-treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics.. Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC-RVH, suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.

Topics: Animals; Antioxidants; Apoptosis; Cardiolipins; Cardiomyopathies; Disease Models, Animal; Enzyme Inhibitors; Female; Hypertension, Renovascular; Magnetic Resonance Angiography; Microvessels; Mitochondria, Heart; Mitochondrial Diseases; Multidetector Computed Tomography; Oligopeptides; Random Allocation; Renal Artery Obstruction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sus scrofa; Swine; tert-Butylhydroperoxide; Ventricular Dysfunction, Left; Ventricular Remodeling

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.

Topics: Angioplasty; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Atherosclerosis; Blotting, Western; Chemokine CCL2; Female; Glomerular Filtration Rate; Kidney; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oligopeptides; Oxidative Stress; Receptors, Cell Surface; Renal Artery Obstruction; Renal Circulation; Swine; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A